Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection.These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates.They are expl...Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection.These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates.They are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance,making them an invaluable asset in the era of antibiotic resistance.Numerous depolymerases have been investigated preclinically,with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection models.Additionally,some formulation approaches have been developed for improved stability and activity of depolymerases.However,depolymerase formulation is limited to liquid dosage form and remains in its infancy,posing a significant hurdle to their clinical translation,compounded by challenges in their applicability and manufacturing.Future development must address these obstacles for clinical utility.Here,after unravelling the history,diversity,and therapeutic use of depolymerases,we summarized the preclinical efficacy and existing formulation findings of recombinant depolymerases.Finally,the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.展开更多
The global increase in the prevalence of drug-resistant bacteria has necessitated the development of alternative treatments that do not rely on conventional antimicrobial agents.Using bacteriophage-derived lytic enzym...The global increase in the prevalence of drug-resistant bacteria has necessitated the development of alternative treatments that do not rely on conventional antimicrobial agents.Using bacteriophage-derived lytic enzymes in antibacterial therapy shows promise;however,a thorough comparison and evaluation of their bactericidal efficacy are lacking.This study aimed to compare and investigate the bactericidal activity and spectrum of such lytic enzymes,with the goal of harnessing them for antibacterial therapy.First,we examined the bactericidal activity of spanins,endolysins,and holins derived from 2 Escherichia coli model phages,T1 and T7.Among these,T1-spanin exhibited the highest bactericidal activity against E.coli.Subsequently,we expressed T1-spanin within bacterial cells and assessed its bactericidal activity.T1-spanin showed potent bactericidal activity against all clinical isolates tested,including bacterial strains of 111 E.coli,2 Acinetobacter spp.,3 Klebsiella spp.,and 3 Pseudomonas aeruginosa.In contrast,T1 phage-derived endolysin showed bactericidal activity against E.coli and P.aeruginosa,yet its efficacy against other bacteria was inferior to that of T1-spanin.Finally,we developed a phage-based technology to introduce the T1-spanin gene into target bacteria.The synthesized non-proliferative phage exhibited strong antibacterial activity against the targeted bacteria.The potent bactericidal activity exhibited by spanins,combined with the novel phage synthetic technology,holds promise for the development of innovative antimicrobial agents.展开更多
基金This work was supported by the University Grants Committee,Hong Kong SAR Government(No.14112921,China).The support of HKPFS from the University Grants Committee to HonglanWang was greatly acknowledged.
文摘Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection.These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates.They are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance,making them an invaluable asset in the era of antibiotic resistance.Numerous depolymerases have been investigated preclinically,with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection models.Additionally,some formulation approaches have been developed for improved stability and activity of depolymerases.However,depolymerase formulation is limited to liquid dosage form and remains in its infancy,posing a significant hurdle to their clinical translation,compounded by challenges in their applicability and manufacturing.Future development must address these obstacles for clinical utility.Here,after unravelling the history,diversity,and therapeutic use of depolymerases,we summarized the preclinical efficacy and existing formulation findings of recombinant depolymerases.Finally,the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.
基金supported by the Japan Agency for Medical Research and Development under grant numbers JP23wm0325065,JP22fk0108532,JP21fk0108496,and JP21 wm0325022 to K.K.grant number JP21gm1610002 to L.C.and K.K.JSPS KAKENHI grants numbers 21H02110 and 21K19666 to K.K.
文摘The global increase in the prevalence of drug-resistant bacteria has necessitated the development of alternative treatments that do not rely on conventional antimicrobial agents.Using bacteriophage-derived lytic enzymes in antibacterial therapy shows promise;however,a thorough comparison and evaluation of their bactericidal efficacy are lacking.This study aimed to compare and investigate the bactericidal activity and spectrum of such lytic enzymes,with the goal of harnessing them for antibacterial therapy.First,we examined the bactericidal activity of spanins,endolysins,and holins derived from 2 Escherichia coli model phages,T1 and T7.Among these,T1-spanin exhibited the highest bactericidal activity against E.coli.Subsequently,we expressed T1-spanin within bacterial cells and assessed its bactericidal activity.T1-spanin showed potent bactericidal activity against all clinical isolates tested,including bacterial strains of 111 E.coli,2 Acinetobacter spp.,3 Klebsiella spp.,and 3 Pseudomonas aeruginosa.In contrast,T1 phage-derived endolysin showed bactericidal activity against E.coli and P.aeruginosa,yet its efficacy against other bacteria was inferior to that of T1-spanin.Finally,we developed a phage-based technology to introduce the T1-spanin gene into target bacteria.The synthesized non-proliferative phage exhibited strong antibacterial activity against the targeted bacteria.The potent bactericidal activity exhibited by spanins,combined with the novel phage synthetic technology,holds promise for the development of innovative antimicrobial agents.
