The Pharmacokinetics informations of aminoglycosides, their monograph and clinical Pharmacokinetics parameters are reported in this review. The Aminoglycosides are highly polarity and in reserve for serious infections...The Pharmacokinetics informations of aminoglycosides, their monograph and clinical Pharmacokinetics parameters are reported in this review. The Aminoglycosides are highly polarity and in reserve for serious infections caused by aerobic gram negative bacteria and some gram positive bacteria but their toxicity are major limitations in clinical use.展开更多
Aminoglycosides are a family of antibiotics with important applications in veterinary medicine. Their ionic character, the similarity structures and the high polarity due to the presence of two or more amino and hydro...Aminoglycosides are a family of antibiotics with important applications in veterinary medicine. Their ionic character, the similarity structures and the high polarity due to the presence of two or more amino and hydroxyl groups cause a difficulty in separation and make these compounds poorly retained on the reversed phase column. An analytical method for the separation and detection of 12 aminoglycosides has been optimized using two kinds of chromatographic conditions (HILIC, Ion pairing). In Hydrophilic Interaction, ZIC_HILIC column was used, by which the following parameters for the mobile phase were evaluated: concentration of ammonium acetate buffer, percentage of formic acid and effect of acid type. The maximum and adequate concentration of ammonium acetate for the majority of analytes was set to 30 mM. The percentage 0.1% of formic acid increases the response for the majority of analytes. On the other side, the use of 0.1% of trifluoroacetic acid improves the response when compared with the response obtained with 0.1% of formic acid except for Spectinomycin Dihydrostreptomycin and Streptomycin. For ion pairing chromatography, the concentration of pentafluoropropionic acid was tested and the greatest value appeared to be 9.2 mM. Therefore, the comparison between the two separation methods shows that the response area of the majority of analytes tested increases when using the ion pair mode. Also, the high value of S/N and the lower detection limit (5 - 15 μg m·L﹣1 for most aminoglycosides studied make the ion pairing method more preferable than HILIC interaction.展开更多
Background: Aminoglycosides are used as empirical antibiotic treatment of intraabdominal infections which are caused by Gram negative bacteria and for which the treatment of choice is surgery. Aminoglycosides maintain...Background: Aminoglycosides are used as empirical antibiotic treatment of intraabdominal infections which are caused by Gram negative bacteria and for which the treatment of choice is surgery. Aminoglycosides maintain good efficacy against these bacteria and reduce the need for prescribing fluoroquinolone, cephalosporin and carbapenem antibiotics which contribute to the development of resistant bacterial strains. In recent years, several clinical trials and international guidelines have advised against the use of aminoglycosides owing largely to doubts about their effectiveness and to the concern for their known nephrotoxicity and ototoxicity. Aim: In our study, we aimed to prove whether aminoglycosides are appropriate agents in the treatment of acute appendicitis. Methods: Retrospectively, patients with acute appendicitis we included in the trial. Demographic characteristics, comorbidities, clinical signs and symptoms, the type of antibiotic and surgical treatment were analyzed. The effect of independent variables on the occurrence of complications was calculated using Student’s T-test and Fisher’s precise test. The effect of aminoglycosides on the loss of kidney function was determined by means of a linear regression method. Results: 300 patients proved acute appendicitis were included in the study. Univariate statistical analysis showed that the risk factors for postoperative complications in treating acute appendicitis were: age over 76 years (p Conclusion: Aminoglycoside antibiotics are a safe and effective treatment of acute appendicitis;our not published data are positive of AGs use in acute cholecystitis and left colon diverticulitis which requires surgery. If used for a limited time period, they do not increase the risk for kidney injury and remain a stable low level of all over complications.展开更多
A novel method to prepare guanidine substituted aminoglycoside derivatives was developed.Free guanidine reacted with Cbz-protected aminoglycosides to produce guanidinylcarbonyl substituted derivatives.A methoxycarbony...A novel method to prepare guanidine substituted aminoglycoside derivatives was developed.Free guanidine reacted with Cbz-protected aminoglycosides to produce guanidinylcarbonyl substituted derivatives.A methoxycarbonyl-protected intermediate was isolated,and the mechanism of guanidinylcarbonyl modification was proposed.With this method,six per- or part-guanidylcarbonyl substituted aminoglycosides were successfully obtained in good yields.Their in vitro antibacterial activities were essayed.展开更多
A series of urea-linked hydroxyl-alkylamine derivatives of aminoglycosides have been obtained by modification of neamine （1）, kanamycin （2） and ribostamycin （3） at 1, 6＇ and 3 N-sites, respectively, through se...A series of urea-linked hydroxyl-alkylamine derivatives of aminoglycosides have been obtained by modification of neamine （1）, kanamycin （2） and ribostamycin （3） at 1, 6＇ and 3 N-sites, respectively, through selective cyclization and nucleophilic ring-opening of cyclic carbamates. All the products showed no noticeable activity in the antibiotic test in vitro. The result suggests that the urea-linked hydroxyl-alkylamine derivatives of aminoglycosides may not be suitable structures for the enhancement of antibiotic activity.展开更多
Objective:To explore the antiviral activity of antibiotic compounds,mainly aminoglycosides and tetracyclines against Japanese encephalitis virus(JEV) induced infection in vitro.Methods:Antiviral activity were evaluate...Objective:To explore the antiviral activity of antibiotic compounds,mainly aminoglycosides and tetracyclines against Japanese encephalitis virus(JEV) induced infection in vitro.Methods:Antiviral activity were evaluated against JEV using cytopathic effect inhibition assay,virus yield reduction assay,caspase 3 level,extracellular viral detection by antigen capture ELISA and viral RNA levels.Roults:JEV induced cytopathic effect along with reduction of viral progeny plaque formation indicated antiviral potential of the compounds suggesting that antibiotics had broad spectrum activity.Doxycycline and kanamycin administration in dose dependent manner declined viral RNA replication.Conclusions:The present study shows kanamycin and doxycyclinc can affect virion structure and alter replication causing inhibition of JEV induced pathogenesis in vitro.展开更多
For the purpose of seeking new antibiotics,researchers usually modify the already-existing ones.However,this strategy has been extensively used and is close to its limits,especially in the case of aminoglycosides,and ...For the purpose of seeking new antibiotics,researchers usually modify the already-existing ones.However,this strategy has been extensively used and is close to its limits,especially in the case of aminoglycosides,and it is difficult to find a proper aminoglycoside antibiotic for novel modification.In this paper,we reported the design,synthesis,and evaluation of a series of 5-epi-neamine derivatives based on the structural information of bacterial 16S RNA A-site binding with aminoglycosides.Bioassay results showed that our design strategy was feasible.Our study offers a new way to search for structurally novel aminoglycosides.Meanwhile,our study provides valuable structure-activity relationship information,which will lead to better understanding and exploitation of the drug target,and improved development of new aminoglycoside antibiotics.展开更多
A novel method to prepare guanidine substituted aminoglycoside derivatives was developed. Free guanidine reacted with Cbz-protected aminoglyeosides to produce guanidinylearbonyl substituted derivatives. A methoxycarbo...A novel method to prepare guanidine substituted aminoglycoside derivatives was developed. Free guanidine reacted with Cbz-protected aminoglyeosides to produce guanidinylearbonyl substituted derivatives. A methoxycarbonyl-protected intermediate was isolated, and the mechanism of guanidinylcarbonyl modification was proposed. With this method, six per- or part- guanidylcarbonyl substituted aminoglycosides were successfully obtained in good yields. Their in vitro antibacterial activities were essayed.展开更多
Background and Prupose: Antibiotic resistance is a major global health concern. In addition to the existing data on the prevalence of bacterial resistance to antibiotics, there are patchy data on bacterial resistance ...Background and Prupose: Antibiotic resistance is a major global health concern. In addition to the existing data on the prevalence of bacterial resistance to antibiotics, there are patchy data on bacterial resistance to aminoglycosides in Burkina Faso. In this study, we determined the prevalence of aminoglycoside resistance genes in E. coli, including aac(3)-IIc, aac(6)-Ib and armA in Ouagadougou, and determined which antibiotics in this class are most affected by resistance. Material and Methods: This study was conducted on 216 E. coli strains collected from the biomedical analysis laboratories of Saint Camille and Schiphra hospitals. E. coli strains were isolated from pus and urine samples collected between September 2018 and January 2019. Antibiotic susceptibility testing was performed using aminoglycosides, β-lactams, fluoroquinolones, and sulfonamides. Aminoglycoside resistance genes were detected in strains with at least one aminoglycoside resistance gene using conventional/multiplex PCR. Results: Aminoglycoside resistance was observed in 46.8% (101/216) of strains. The resistance rates were respectively 45.37% for Tobramycin, 32.40% for Gentamicin, 14.81% for Kanamycin, 2.31% for Netilmicin, 1.84% for Neomycin, and 0.46% for Amikacin. PCR showed that 86 strains (85.15%) possessed the aac(3)-IIc gene, 71 strains or 70.30%) possessed the aac(6’)-Ib gene, and nine strains (8.91%) possessed the armA gene. Conclusion: Aminoglycoside resistance in pathogenic E. coli strains is mainly due to the presence of the aac(3’)-IIc and aac(6’)-Ib genes. The presence of armA was first reported in Burkina Faso. Netilmicin, Neomycin and Amikacin are good therapeutic options for treating urinary tract and pus-forming infections.展开更多
Aminoglycosides are concentration-dependent antibiotics exerting a bactericidal effect when concentrations at the site of infection are equal to or greater than 5 times the minimum inhibitory concentrations(MIC).When ...Aminoglycosides are concentration-dependent antibiotics exerting a bactericidal effect when concentrations at the site of infection are equal to or greater than 5 times the minimum inhibitory concentrations(MIC).When administered intravenously,they exhibit poor lung penetration and high systemic renal and ototoxicity,imposing to restrict their administration to 5 days.Experimental studies conducted in anesthetized and mechanically ventilated sheep and pigs provide evidence that high doses of nebulized aminoglycosides induce a rapid and potent bacterial killing in the infected lung parenchyma.They also confirm that the alveolar-capillary membrane,either normal or injured by the infectious process,restricts the penetration of intravenous aminoglycosides in the infected lung parenchyma,precluding a bactericidal effect at the site of infection.However,injury of the alveolar-capillary membrane promotes the systemic diffusion of nebulized aminoglycosides.Based on experimental data obtained in animals with inoculation pneumonia,it challenges the classical belief that nebulization protects against systemic toxicity.Loss of lung aeration decreases the lung penetration of nebulized aminoglycosides.Nevertheless,lung tissue concentrations measured in non-aerated lung regions with severe and extended pneumonia are most often greater than 5 times the MICs,resulting in a bactericidal effect followed by a progressive pulmonary reaeration.It is likely that the penetration into the consolidated lung,results from the bronchial diffusion of nebulized aminoglycosides toward adjacent non-aerated infected alveolar spaces and their penetration into mechanical ventilation-induced intraparenchymal pseudocysts and distended bronchioles.In animals receiving nebulized aminoglycosides,epithelial lining fluid concentrations grossly overestimate lung interstitial fluid concentrations because of the bronchial contamination of the distal tip of the bronchoscope during the bronchoalveolar procedures.Lung microdialysis is the only technique able to accurately assess lung pharmacokinetics in animals with inoculation pneumonia treated by nebulized aminoglycosides.In 2024,the European Investigators Network for Nebulized Antibiotics in Ventilator-associated Pneumonia(ENAVAP)called for the creation of an international research network for Lung Microdialysis applied to Nebulized Antibiotics(LUMINA)to promote multicentered,experimental,randomized,and controlled studies addressing lung pharmacokinetics of intravenous vs.nebulized antibiotics,using different dosing and ventilator settings.展开更多
In general,the initiation or closure of antibiotic biosynthesis is determined by regulatory proteins,but most of their mechanisms of action remain unknown.The 2-deoxystreptamine-containing aminoglycosides(2-DOS AGs)fo...In general,the initiation or closure of antibiotic biosynthesis is determined by regulatory proteins,but most of their mechanisms of action remain unknown.The 2-deoxystreptamine-containing aminoglycosides(2-DOS AGs)form a unique category among antibiotics.Genomic analysis revealed that a group of hypothetical regulatory genes represented by neo I are widely distributed in the biosynthetic gene clusters(BGCs)of natural products from Streptomyces species,including several 2-DOS AGs.Only limited knowledge is available for the roles of Neo Itype regulators although neomycin and some of the related AGs have been developed as therapeutic drugs for decades.This study focuses on the functional determination of neo I and its homologues situated in the BGCs of six AGs.We found that the yield of neomycin in neo I disruption mutant(Δneo I)increased by 50%compared to the wild-type(WT)strain((420.6±44.1)mg L^(-1)),while it was partially restored by the complementation of neo I,demonstrating that Neo I acted as a repressor in neomycin biosynthesis.Further electrophoretic mobility shift assays(EMSAs)and DNase I footprinting assays indicated that Neo I could specifically bind to the promoter region between neo E and neo I with conserved nucleotides(5'-CVHYMRCHDKAGYGGACR-3'),as determined by site-directed mutagenesis.Interestingly,cross-bindings of the Neo I homologues from the six different BGCs to their corresponding DNA targets were manifested,and the five exogenous Neo I homologues could complement Neo I function of repressing neomycin biosynthesis.Our results suggested that Neo I-type regulators represent widespread and conservative regulatory characteristics in the biosynthesis of 2-DOS AGs,which would be significant for optimizing the biosynthetic pathways of valuable commercialized aminoglycoside antibiotics.展开更多
Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chron...Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chronic implant infections in clinical,only few drugs are effective in clearing persisters and formed biofilms.Here,felodipine,a dihydropyridine calcium channel blocker,was reported for the first time to have antibacterial effects against MRSA,biofilm,and persisters.Even after continuous exposure to sub-lethal concentrations of felodipine,bacteria are less likely to develop resistance.Besides,low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance(aacA-aphD).Next,biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters.Furthermore,the result of protein profiling,and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence(agrABC),biofilm formation and TCA cycle.Then,molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease,which could lead to substantial protein degradation.Furthermore,murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response.In conclusion,low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA,biofilm,and persisters.展开更多
Resistance to pentavalent antimonial drugs and the lack of vaccines make it urgent to find novel therapeutic options to treat Leishmaniasis, a tropical disease caused by the Leishmania protozoan parasite. The study re...Resistance to pentavalent antimonial drugs and the lack of vaccines make it urgent to find novel therapeutic options to treat Leishmaniasis, a tropical disease caused by the Leishmania protozoan parasite. The study reported here is to investigate if Streptomycin, an aminoglycoside, and Amphotericin B, the second-line treatment drug, exhibit antileishmanial activity through a similar mechanism. By using MOE (Molecular Operating Environment), we performed molecular docking studies on these drugs binding to a range of targets including ribosome targets in Leishmania and H. sapiens. Our study shows that the two drugs do not bind to the same pockets in Leishmania targets but to the same pockets in the human ribosome, with some differences in interactions. Moreover, our 2D maps indicated that Amphotericin B binds to the A-site in the human cytoplasmic ribosome, whereas streptomycin does not.展开更多
The human ear is a delicate sensory apparatus of hearing for normal communication, and its proper functioning is highly dependent on mitochondrial oxidative phosphorylation. The first mitochondrial point mutation for ...The human ear is a delicate sensory apparatus of hearing for normal communication, and its proper functioning is highly dependent on mitochondrial oxidative phosphorylation. The first mitochondrial point mutation for nonsyndromic and aminoglycoside-induced hearing loss was identified in 1993. Since then a number of inherited mitochondrial mutations have been implicated in hearing loss. Most of the molecular defects responsible for mitochondrial disorder-associated hearing loss are mutations in the 12S rRNA gene and tRNA genes. In this review, after a short description of normal hearing mechanisms and mitochondrial genetics, we outline the recent advances that have been made in the identification of deafness-associated mitochondrial mutations, and discuss how mitochondrial dysfunction contributes to hearing loss.展开更多
Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world...Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12 S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to Am An-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently,exposure to Am An can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to Am An ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.展开更多
Aminoglycosides are one of the categories of antibiotics most frequently used in treating several cattle diseases at the Central Cattle Breeding and Dairy Farm (CCBDF), Savar,Dhaka,Bangladesh. Untreated veterinary cli...Aminoglycosides are one of the categories of antibiotics most frequently used in treating several cattle diseases at the Central Cattle Breeding and Dairy Farm (CCBDF), Savar,Dhaka,Bangladesh. Untreated veterinary clinical healthcare waste (VCHW) of diseased cattle at CCBDF which directly disposed to surrounding may contribute to the antibiotic resistant bacteria pollution (ARB) pollution. The investigation analyses the role of VCHW of CCBDF in spreading ARB. Here we studied:1) veterinary clinical data and antibiotics treatment history;2) total and resistant bacteria counts in fecal samples of healthy and diseased cattles as well as VCHW of CCBDF;and 3) finally, data analysis to estimate the burden of VCHW of CCBDF in the pollution of environment with aminoglycoside antibiotics resistant bacteria. The results conclusively demonstrate the spread of 3 different aminoglycoside antibiotics, namely genta- mycin, kanamycin and streptomycin resistant bacte- ria in the surrounding environment alarmingly with high significant value (p < 0.01 - 0.05). This study re- veals the risks to the cattle as well as public health posed by the random VCHW disposal at the CCBDF, Bangladesh.展开更多
Context: Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem in developing countries such as the Democratic Republic of Congo (DRC), which continues to face the emergence of MDR-TB cases. B...Context: Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem in developing countries such as the Democratic Republic of Congo (DRC), which continues to face the emergence of MDR-TB cases. Because of the ototoxic effects of AGs, the World Health Organization (WHO) has recommended the introduction of the bedaquiline regimen. However, very few data are available regarding the susceptibility of bedaquiline to induce hearing loss, hence the present study set out to compare the AG-based regimen and the bedaquiline-based regimen in the occurrence of hearing loss in MDR-TB patients. Methods: This is a prospective multicenter cohort study that included 335 MDR-TB patients, performed in Kinshasa (DRC) during the period from January 2020 to January 2021. Sociodemographic, clinical, biological and audiometric data were analyzed using Stata 17. Repeated-measures analysis of variance was used to compare changes in the degree of hearing loss over time between the two groups of patients on AG and bedaquiline regimens. The double-difference method was estimated using regression with fixed-effects. A p value < 0.05 was considered the threshold for statistical significance. Results: The degree of hearing loss was similar between the two groups at the first month [AGs (28 dB) vs BDQ (30 dB);p = 0.298]. At six months, the mean degree of hearing loss was significantly greater in the aminoglycoside regimen group [AGs (60.5 dB) vs BDQ (44 dB);p < 0.001]. The double difference was significant, with a greater increase in hearing loss in the AGs group (diff-in-diff 18.3;p < 0.001). After adjustment for age and serum albumin, the group receiving the AG-based regimen had a 2-point greater worsening than those with bedaquiline at the sixth month (diff-in-diff 19.8;p Conclusion: Hearing loss is frequent with both treatment regimens, but more marked with the Aminoglycoside-based regimen. Thus, bedaquiline should also benefit for audiometric monitoring in future MDR-TB patients.展开更多
Aim To develop a novel selective protection strategy for the synthesis of ribostamycin cyclic carbamate derivatives. Methods Ribostamycin protected by carbobenzoxy group was treated with Nail, to give different protec...Aim To develop a novel selective protection strategy for the synthesis of ribostamycin cyclic carbamate derivatives. Methods Ribostamycin protected by carbobenzoxy group was treated with Nail, to give different protected intermediates under respective controllable cyclization reaction conditions. New ribostamycin derivative was obtained after the cleavage of carbobenzoxy groups. Result The novel selective protection of ribostamycin was achieved by the synthesis of protected intermediates. New ribostamycin derivative was obtained, but showed no expected antibacterial activity. Conclusion Several ribostamycin cyclic carbamate derivatives were obtained by novel selective protection strategy, which shows the practicability and convenience of the protection strategy. But these new ribostamycin derivatives containing cyclic carbamates structure may not be an ideal leading compound for antibiotic activity.展开更多
To design and synthesize neamine analogues modified at 5 position offing Ⅱ, which could improve the binding affinity of aminoglycosides to 16S RNA. Started from neomycin B, modified neamine analogues were synthesized...To design and synthesize neamine analogues modified at 5 position offing Ⅱ, which could improve the binding affinity of aminoglycosides to 16S RNA. Started from neomycin B, modified neamine analogues were synthesized through organic reactions such as hydrolysis, protection, nucleophilic substitution, deprotection and reduction. The interaction of the target compounds with A-site RNA in E. coli. ribosome （16S RNA） was determined by surface plasmon resonance （SPR）, respectively. Six target compounds were synthesized. Some of them showed antibacterial activities and enhanced affinity to 16S RNA at 10^-3M in vitro. Introduction amino or aliphatic amino group at 5 position offing Ⅱ in neamine would maintained antibacterial activities as well as increase binding affinity to 16S RNA. Furthermore, there is almost no influence on the stability of drug/16S RNA complex by inverting the configuration of 5-hydroxyl group at ring Ⅱ.展开更多
文摘The Pharmacokinetics informations of aminoglycosides, their monograph and clinical Pharmacokinetics parameters are reported in this review. The Aminoglycosides are highly polarity and in reserve for serious infections caused by aerobic gram negative bacteria and some gram positive bacteria but their toxicity are major limitations in clinical use.
文摘Aminoglycosides are a family of antibiotics with important applications in veterinary medicine. Their ionic character, the similarity structures and the high polarity due to the presence of two or more amino and hydroxyl groups cause a difficulty in separation and make these compounds poorly retained on the reversed phase column. An analytical method for the separation and detection of 12 aminoglycosides has been optimized using two kinds of chromatographic conditions (HILIC, Ion pairing). In Hydrophilic Interaction, ZIC_HILIC column was used, by which the following parameters for the mobile phase were evaluated: concentration of ammonium acetate buffer, percentage of formic acid and effect of acid type. The maximum and adequate concentration of ammonium acetate for the majority of analytes was set to 30 mM. The percentage 0.1% of formic acid increases the response for the majority of analytes. On the other side, the use of 0.1% of trifluoroacetic acid improves the response when compared with the response obtained with 0.1% of formic acid except for Spectinomycin Dihydrostreptomycin and Streptomycin. For ion pairing chromatography, the concentration of pentafluoropropionic acid was tested and the greatest value appeared to be 9.2 mM. Therefore, the comparison between the two separation methods shows that the response area of the majority of analytes tested increases when using the ion pair mode. Also, the high value of S/N and the lower detection limit (5 - 15 μg m·L﹣1 for most aminoglycosides studied make the ion pairing method more preferable than HILIC interaction.
文摘Background: Aminoglycosides are used as empirical antibiotic treatment of intraabdominal infections which are caused by Gram negative bacteria and for which the treatment of choice is surgery. Aminoglycosides maintain good efficacy against these bacteria and reduce the need for prescribing fluoroquinolone, cephalosporin and carbapenem antibiotics which contribute to the development of resistant bacterial strains. In recent years, several clinical trials and international guidelines have advised against the use of aminoglycosides owing largely to doubts about their effectiveness and to the concern for their known nephrotoxicity and ototoxicity. Aim: In our study, we aimed to prove whether aminoglycosides are appropriate agents in the treatment of acute appendicitis. Methods: Retrospectively, patients with acute appendicitis we included in the trial. Demographic characteristics, comorbidities, clinical signs and symptoms, the type of antibiotic and surgical treatment were analyzed. The effect of independent variables on the occurrence of complications was calculated using Student’s T-test and Fisher’s precise test. The effect of aminoglycosides on the loss of kidney function was determined by means of a linear regression method. Results: 300 patients proved acute appendicitis were included in the study. Univariate statistical analysis showed that the risk factors for postoperative complications in treating acute appendicitis were: age over 76 years (p Conclusion: Aminoglycoside antibiotics are a safe and effective treatment of acute appendicitis;our not published data are positive of AGs use in acute cholecystitis and left colon diverticulitis which requires surgery. If used for a limited time period, they do not increase the risk for kidney injury and remain a stable low level of all over complications.
基金National Basic Research Program(973 Program, Grant No.2004CB518904)the State New Drug Innovation (Grant No.2009ZX09301-010,2009ZX09103 -044).
文摘A novel method to prepare guanidine substituted aminoglycoside derivatives was developed.Free guanidine reacted with Cbz-protected aminoglycosides to produce guanidinylcarbonyl substituted derivatives.A methoxycarbonyl-protected intermediate was isolated,and the mechanism of guanidinylcarbonyl modification was proposed.With this method,six per- or part-guanidylcarbonyl substituted aminoglycosides were successfully obtained in good yields.Their in vitro antibacterial activities were essayed.
基金National Basic Research Program(973 Program Grant No.2004CB518904)
文摘A series of urea-linked hydroxyl-alkylamine derivatives of aminoglycosides have been obtained by modification of neamine （1）, kanamycin （2） and ribostamycin （3） at 1, 6＇ and 3 N-sites, respectively, through selective cyclization and nucleophilic ring-opening of cyclic carbamates. All the products showed no noticeable activity in the antibiotic test in vitro. The result suggests that the urea-linked hydroxyl-alkylamine derivatives of aminoglycosides may not be suitable structures for the enhancement of antibiotic activity.
文摘Objective:To explore the antiviral activity of antibiotic compounds,mainly aminoglycosides and tetracyclines against Japanese encephalitis virus(JEV) induced infection in vitro.Methods:Antiviral activity were evaluated against JEV using cytopathic effect inhibition assay,virus yield reduction assay,caspase 3 level,extracellular viral detection by antigen capture ELISA and viral RNA levels.Roults:JEV induced cytopathic effect along with reduction of viral progeny plaque formation indicated antiviral potential of the compounds suggesting that antibiotics had broad spectrum activity.Doxycycline and kanamycin administration in dose dependent manner declined viral RNA replication.Conclusions:The present study shows kanamycin and doxycyclinc can affect virion structure and alter replication causing inhibition of JEV induced pathogenesis in vitro.
基金supported by the National Natural Science Foundation of China(No.21877006).
文摘For the purpose of seeking new antibiotics,researchers usually modify the already-existing ones.However,this strategy has been extensively used and is close to its limits,especially in the case of aminoglycosides,and it is difficult to find a proper aminoglycoside antibiotic for novel modification.In this paper,we reported the design,synthesis,and evaluation of a series of 5-epi-neamine derivatives based on the structural information of bacterial 16S RNA A-site binding with aminoglycosides.Bioassay results showed that our design strategy was feasible.Our study offers a new way to search for structurally novel aminoglycosides.Meanwhile,our study provides valuable structure-activity relationship information,which will lead to better understanding and exploitation of the drug target,and improved development of new aminoglycoside antibiotics.
基金Foundation items： National Basic Research Program （973 Program, Grant No. 2004CB518904） and the State New Drug Innovation Grant No. 2009ZX09301-010, 2009ZX09103-044）.
文摘A novel method to prepare guanidine substituted aminoglycoside derivatives was developed. Free guanidine reacted with Cbz-protected aminoglyeosides to produce guanidinylearbonyl substituted derivatives. A methoxycarbonyl-protected intermediate was isolated, and the mechanism of guanidinylcarbonyl modification was proposed. With this method, six per- or part- guanidylcarbonyl substituted aminoglycosides were successfully obtained in good yields. Their in vitro antibacterial activities were essayed.
文摘Background and Prupose: Antibiotic resistance is a major global health concern. In addition to the existing data on the prevalence of bacterial resistance to antibiotics, there are patchy data on bacterial resistance to aminoglycosides in Burkina Faso. In this study, we determined the prevalence of aminoglycoside resistance genes in E. coli, including aac(3)-IIc, aac(6)-Ib and armA in Ouagadougou, and determined which antibiotics in this class are most affected by resistance. Material and Methods: This study was conducted on 216 E. coli strains collected from the biomedical analysis laboratories of Saint Camille and Schiphra hospitals. E. coli strains were isolated from pus and urine samples collected between September 2018 and January 2019. Antibiotic susceptibility testing was performed using aminoglycosides, β-lactams, fluoroquinolones, and sulfonamides. Aminoglycoside resistance genes were detected in strains with at least one aminoglycoside resistance gene using conventional/multiplex PCR. Results: Aminoglycoside resistance was observed in 46.8% (101/216) of strains. The resistance rates were respectively 45.37% for Tobramycin, 32.40% for Gentamicin, 14.81% for Kanamycin, 2.31% for Netilmicin, 1.84% for Neomycin, and 0.46% for Amikacin. PCR showed that 86 strains (85.15%) possessed the aac(3)-IIc gene, 71 strains or 70.30%) possessed the aac(6’)-Ib gene, and nine strains (8.91%) possessed the armA gene. Conclusion: Aminoglycoside resistance in pathogenic E. coli strains is mainly due to the presence of the aac(3’)-IIc and aac(6’)-Ib genes. The presence of armA was first reported in Burkina Faso. Netilmicin, Neomycin and Amikacin are good therapeutic options for treating urinary tract and pus-forming infections.
文摘Aminoglycosides are concentration-dependent antibiotics exerting a bactericidal effect when concentrations at the site of infection are equal to or greater than 5 times the minimum inhibitory concentrations(MIC).When administered intravenously,they exhibit poor lung penetration and high systemic renal and ototoxicity,imposing to restrict their administration to 5 days.Experimental studies conducted in anesthetized and mechanically ventilated sheep and pigs provide evidence that high doses of nebulized aminoglycosides induce a rapid and potent bacterial killing in the infected lung parenchyma.They also confirm that the alveolar-capillary membrane,either normal or injured by the infectious process,restricts the penetration of intravenous aminoglycosides in the infected lung parenchyma,precluding a bactericidal effect at the site of infection.However,injury of the alveolar-capillary membrane promotes the systemic diffusion of nebulized aminoglycosides.Based on experimental data obtained in animals with inoculation pneumonia,it challenges the classical belief that nebulization protects against systemic toxicity.Loss of lung aeration decreases the lung penetration of nebulized aminoglycosides.Nevertheless,lung tissue concentrations measured in non-aerated lung regions with severe and extended pneumonia are most often greater than 5 times the MICs,resulting in a bactericidal effect followed by a progressive pulmonary reaeration.It is likely that the penetration into the consolidated lung,results from the bronchial diffusion of nebulized aminoglycosides toward adjacent non-aerated infected alveolar spaces and their penetration into mechanical ventilation-induced intraparenchymal pseudocysts and distended bronchioles.In animals receiving nebulized aminoglycosides,epithelial lining fluid concentrations grossly overestimate lung interstitial fluid concentrations because of the bronchial contamination of the distal tip of the bronchoscope during the bronchoalveolar procedures.Lung microdialysis is the only technique able to accurately assess lung pharmacokinetics in animals with inoculation pneumonia treated by nebulized aminoglycosides.In 2024,the European Investigators Network for Nebulized Antibiotics in Ventilator-associated Pneumonia(ENAVAP)called for the creation of an international research network for Lung Microdialysis applied to Nebulized Antibiotics(LUMINA)to promote multicentered,experimental,randomized,and controlled studies addressing lung pharmacokinetics of intravenous vs.nebulized antibiotics,using different dosing and ventilator settings.
基金supported by the National Natural Science Foundation of China (32170043,82173720)the National Key Research and Development Program of China (2020YFA0907800)。
文摘In general,the initiation or closure of antibiotic biosynthesis is determined by regulatory proteins,but most of their mechanisms of action remain unknown.The 2-deoxystreptamine-containing aminoglycosides(2-DOS AGs)form a unique category among antibiotics.Genomic analysis revealed that a group of hypothetical regulatory genes represented by neo I are widely distributed in the biosynthetic gene clusters(BGCs)of natural products from Streptomyces species,including several 2-DOS AGs.Only limited knowledge is available for the roles of Neo Itype regulators although neomycin and some of the related AGs have been developed as therapeutic drugs for decades.This study focuses on the functional determination of neo I and its homologues situated in the BGCs of six AGs.We found that the yield of neomycin in neo I disruption mutant(Δneo I)increased by 50%compared to the wild-type(WT)strain((420.6±44.1)mg L^(-1)),while it was partially restored by the complementation of neo I,demonstrating that Neo I acted as a repressor in neomycin biosynthesis.Further electrophoretic mobility shift assays(EMSAs)and DNase I footprinting assays indicated that Neo I could specifically bind to the promoter region between neo E and neo I with conserved nucleotides(5'-CVHYMRCHDKAGYGGACR-3'),as determined by site-directed mutagenesis.Interestingly,cross-bindings of the Neo I homologues from the six different BGCs to their corresponding DNA targets were manifested,and the five exogenous Neo I homologues could complement Neo I function of repressing neomycin biosynthesis.Our results suggested that Neo I-type regulators represent widespread and conservative regulatory characteristics in the biosynthesis of 2-DOS AGs,which would be significant for optimizing the biosynthetic pathways of valuable commercialized aminoglycoside antibiotics.
基金supported by the National Natural Science Foundation of China(Grant No.82172464,82172453,81972086)National Key Research and Development Project of China(Grant No.2020YFC1107500,2020YFC1107503)+4 种基金The Shanghai Rising-Star Program(21QA1405500)Shanghai“Rising Stars of Medical Talent”Youth Development Program(Youth Medical Talents-Specialist Program)(Grant No.2019-72)“Technology Innovation Action Plan”Key Project of Shanghai Science and Technology Commission(Grant No.19411962800)Shanghai municipal education commission-Gaofeng clinical medicine grant support(Grant No.20161423)NSFC Advancing Targeted Projects(RJTJ-JX-005,RJTJ22-RC-011).
文摘Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chronic implant infections in clinical,only few drugs are effective in clearing persisters and formed biofilms.Here,felodipine,a dihydropyridine calcium channel blocker,was reported for the first time to have antibacterial effects against MRSA,biofilm,and persisters.Even after continuous exposure to sub-lethal concentrations of felodipine,bacteria are less likely to develop resistance.Besides,low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance(aacA-aphD).Next,biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters.Furthermore,the result of protein profiling,and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence(agrABC),biofilm formation and TCA cycle.Then,molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease,which could lead to substantial protein degradation.Furthermore,murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response.In conclusion,low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA,biofilm,and persisters.
文摘Resistance to pentavalent antimonial drugs and the lack of vaccines make it urgent to find novel therapeutic options to treat Leishmaniasis, a tropical disease caused by the Leishmania protozoan parasite. The study reported here is to investigate if Streptomycin, an aminoglycoside, and Amphotericin B, the second-line treatment drug, exhibit antileishmanial activity through a similar mechanism. By using MOE (Molecular Operating Environment), we performed molecular docking studies on these drugs binding to a range of targets including ribosome targets in Leishmania and H. sapiens. Our study shows that the two drugs do not bind to the same pockets in Leishmania targets but to the same pockets in the human ribosome, with some differences in interactions. Moreover, our 2D maps indicated that Amphotericin B binds to the A-site in the human cytoplasmic ribosome, whereas streptomycin does not.
基金We acknowledge the support by a grant award from Jiangsu Natural Science Foundation,Grant No.BK2006247grant awards from Jiangsu Health Administration,Grant No.WK0623 and K200502.
文摘The human ear is a delicate sensory apparatus of hearing for normal communication, and its proper functioning is highly dependent on mitochondrial oxidative phosphorylation. The first mitochondrial point mutation for nonsyndromic and aminoglycoside-induced hearing loss was identified in 1993. Since then a number of inherited mitochondrial mutations have been implicated in hearing loss. Most of the molecular defects responsible for mitochondrial disorder-associated hearing loss are mutations in the 12S rRNA gene and tRNA genes. In this review, after a short description of normal hearing mechanisms and mitochondrial genetics, we outline the recent advances that have been made in the identification of deafness-associated mitochondrial mutations, and discuss how mitochondrial dysfunction contributes to hearing loss.
基金supported by the project from National Basic Research Priorities Program of China (2014CB541702)National Natural Science Foundation of China (31671305)
文摘Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12 S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to Am An-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently,exposure to Am An can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to Am An ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.
文摘Aminoglycosides are one of the categories of antibiotics most frequently used in treating several cattle diseases at the Central Cattle Breeding and Dairy Farm (CCBDF), Savar,Dhaka,Bangladesh. Untreated veterinary clinical healthcare waste (VCHW) of diseased cattle at CCBDF which directly disposed to surrounding may contribute to the antibiotic resistant bacteria pollution (ARB) pollution. The investigation analyses the role of VCHW of CCBDF in spreading ARB. Here we studied:1) veterinary clinical data and antibiotics treatment history;2) total and resistant bacteria counts in fecal samples of healthy and diseased cattles as well as VCHW of CCBDF;and 3) finally, data analysis to estimate the burden of VCHW of CCBDF in the pollution of environment with aminoglycoside antibiotics resistant bacteria. The results conclusively demonstrate the spread of 3 different aminoglycoside antibiotics, namely genta- mycin, kanamycin and streptomycin resistant bacte- ria in the surrounding environment alarmingly with high significant value (p < 0.01 - 0.05). This study re- veals the risks to the cattle as well as public health posed by the random VCHW disposal at the CCBDF, Bangladesh.
文摘Context: Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem in developing countries such as the Democratic Republic of Congo (DRC), which continues to face the emergence of MDR-TB cases. Because of the ototoxic effects of AGs, the World Health Organization (WHO) has recommended the introduction of the bedaquiline regimen. However, very few data are available regarding the susceptibility of bedaquiline to induce hearing loss, hence the present study set out to compare the AG-based regimen and the bedaquiline-based regimen in the occurrence of hearing loss in MDR-TB patients. Methods: This is a prospective multicenter cohort study that included 335 MDR-TB patients, performed in Kinshasa (DRC) during the period from January 2020 to January 2021. Sociodemographic, clinical, biological and audiometric data were analyzed using Stata 17. Repeated-measures analysis of variance was used to compare changes in the degree of hearing loss over time between the two groups of patients on AG and bedaquiline regimens. The double-difference method was estimated using regression with fixed-effects. A p value < 0.05 was considered the threshold for statistical significance. Results: The degree of hearing loss was similar between the two groups at the first month [AGs (28 dB) vs BDQ (30 dB);p = 0.298]. At six months, the mean degree of hearing loss was significantly greater in the aminoglycoside regimen group [AGs (60.5 dB) vs BDQ (44 dB);p < 0.001]. The double difference was significant, with a greater increase in hearing loss in the AGs group (diff-in-diff 18.3;p < 0.001). After adjustment for age and serum albumin, the group receiving the AG-based regimen had a 2-point greater worsening than those with bedaquiline at the sixth month (diff-in-diff 19.8;p Conclusion: Hearing loss is frequent with both treatment regimens, but more marked with the Aminoglycoside-based regimen. Thus, bedaquiline should also benefit for audiometric monitoring in future MDR-TB patients.
基金The National Basic Research Program(973Program,Grant No.2004CB518904).
文摘Aim To develop a novel selective protection strategy for the synthesis of ribostamycin cyclic carbamate derivatives. Methods Ribostamycin protected by carbobenzoxy group was treated with Nail, to give different protected intermediates under respective controllable cyclization reaction conditions. New ribostamycin derivative was obtained after the cleavage of carbobenzoxy groups. Result The novel selective protection of ribostamycin was achieved by the synthesis of protected intermediates. New ribostamycin derivative was obtained, but showed no expected antibacterial activity. Conclusion Several ribostamycin cyclic carbamate derivatives were obtained by novel selective protection strategy, which shows the practicability and convenience of the protection strategy. But these new ribostamycin derivatives containing cyclic carbamates structure may not be an ideal leading compound for antibiotic activity.
基金National Natural Science Foundation of China(Grant No.20332010)the Ministry of Science and Technology of China(Grant No.2005BA711A04).
文摘To design and synthesize neamine analogues modified at 5 position offing Ⅱ, which could improve the binding affinity of aminoglycosides to 16S RNA. Started from neomycin B, modified neamine analogues were synthesized through organic reactions such as hydrolysis, protection, nucleophilic substitution, deprotection and reduction. The interaction of the target compounds with A-site RNA in E. coli. ribosome （16S RNA） was determined by surface plasmon resonance （SPR）, respectively. Six target compounds were synthesized. Some of them showed antibacterial activities and enhanced affinity to 16S RNA at 10^-3M in vitro. Introduction amino or aliphatic amino group at 5 position offing Ⅱ in neamine would maintained antibacterial activities as well as increase binding affinity to 16S RNA. Furthermore, there is almost no influence on the stability of drug/16S RNA complex by inverting the configuration of 5-hydroxyl group at ring Ⅱ.
