耐甲氧西林金黄色葡萄球菌(MRSA)是金黄色葡萄球菌的一种多重耐药菌株,在1961年首次由英国报道。MRSA的高发病率、高死亡率及多重耐药特点,使其一问世便受到人们的广泛关注。mecA基因编码的青霉素结合蛋2a (PBP2a)正是赋予MRSA广谱耐β...耐甲氧西林金黄色葡萄球菌(MRSA)是金黄色葡萄球菌的一种多重耐药菌株,在1961年首次由英国报道。MRSA的高发病率、高死亡率及多重耐药特点,使其一问世便受到人们的广泛关注。mecA基因编码的青霉素结合蛋2a (PBP2a)正是赋予MRSA广谱耐β-内酰胺类抗生素的关键蛋白。头孢洛林作为第五代头孢菌素,具有广谱抗菌活性,尤其对MRSA表现出显著的抗菌效果。头孢洛林能结合PBP2a变构位点,诱导蛋白质发生构象变化,使活性位点充分暴露,并与活性位点结合,抑制PBP2a的酶活性。这种双重作用机制增强了头孢洛林对MRSA的抗菌活性,使其成为一把针对MRSA的利器。但早在头孢洛林上市(2010年,美国食品和药物监督管理局批准上市)前的1998年,就已发现高水平耐头孢洛林MRSA。人们意识到头孢洛林并不能一劳永逸地解决MRSA,需要更深层次地探究二者之间作用机制,以更好运用好头孢洛林这一武器,延缓MRSA对其广泛耐药的时间。Methicillin-resistant Staphylococcus aureus (MRSA), a multidrug-resistant variant of S. aureus, was initially documented in the United Kingdom in 1961. Characterized by its elevated morbidity, mortality rates, and resistance to multiple antibiotic classes, MRSA rapidly emerged as a major global health threat following its discovery. The molecular basis of its broad-spectrum β-lactam resistance is attributed to the penicillin-binding protein 2a (PBP2a), encoded by the mecA gene. Ceftaroline fosamil, a fifth-generation cephalosporin approved by the U.S. Food and Drug Administration (FDA) in 2010, demonstrates exceptional antibacterial efficacy against MRSA through a unique dual mechanism involving both allosteric modulation and active site inhibition. By binding to the allosteric domain of PBP2a, ceftaroline induces conformational changes that expose the catalytic pocket, enabling subsequent interaction with the active site to irreversibly block its transpeptidase activity—a critical enzyme for bacterial cell wall biosynthesis. This dual-targeting strategy significantly enhances the compound’s bactericidal potency, establishing it as a cornerstone therapy for MRSA infections. Paradoxically, surveillance studies revealed the existence of high-level ceftaroline-resistant MRSA strains as early as 1998, predating the drug’s clinical approval by over a decade. These observations underscore the limitations of relying solely on ceftaroline as a definitive solution for MRSA management. The premature emergence of resistance necessitates a deeper investigation into the dynamic molecular interactions between ceftaroline and its bacterial targets, particularly the structural plasticity of PBP2a and compensatory mutations in auxiliary resistance determinants. Elucidating these mechanisms at atomic resolution is imperative for optimizing therapeutic regimens, designing next-generation β-lactams, and ultimately delaying the trajectory toward pan-resistance in MRSA populations.展开更多
Background The Alere PBP2a SA Culture Colony Test is an FDA-cleared in vitro immunochromatographic assay for rapid detection of penicillin-binding protein2a(PBP2a)in Staphylococcus aureus.Methods We investigated the p...Background The Alere PBP2a SA Culture Colony Test is an FDA-cleared in vitro immunochromatographic assay for rapid detection of penicillin-binding protein2a(PBP2a)in Staphylococcus aureus.Methods We investigated the performance of the PBP2a SA Culture Colony Test with 78 coagulase-negative Staphylococcus(CoNS)isolates from different body sites,with the Vitek 2 Antimicrobial Susceptibility Test(AST)as a reference standard.Results The CoNS species were 62 S.epidermidis;6 S.lugdenensis;3 S.hominis;2 S.capitis;2 S.haemolyticus;and 1 each of S.simulans,S.auricularis,and S.warneri.Of the 78 CoNS isolates,68 showed concordance in the PBP2a IC assay and Vitek 2 AST.Discordance was seen for 10 S.epidermidis isolates,which showed negative in the PBP2a assay,despite oxacillin-resistance detection using the Vitek 2 AST(66.7%sensitivity and 100%specificity).All non-S.epidermidis CoNS were identified with 100%concordance using the PBP2a IC assay and Vitek 2 AST.Conclusion We demonstrated that,while the PBP2a IC assay has low sensitivity in determining the susceptibility of S.epidermidis to oxacillin,it highly accurately predicted the susceptibility of non-S.epidermidis CoNS to oxacillin.The diagnostic accuracy for non-S.epidermidis CoNS needs further assessment with more isolates to confirm our findings.展开更多
文摘耐甲氧西林金黄色葡萄球菌(MRSA)是金黄色葡萄球菌的一种多重耐药菌株,在1961年首次由英国报道。MRSA的高发病率、高死亡率及多重耐药特点,使其一问世便受到人们的广泛关注。mecA基因编码的青霉素结合蛋2a (PBP2a)正是赋予MRSA广谱耐β-内酰胺类抗生素的关键蛋白。头孢洛林作为第五代头孢菌素,具有广谱抗菌活性,尤其对MRSA表现出显著的抗菌效果。头孢洛林能结合PBP2a变构位点,诱导蛋白质发生构象变化,使活性位点充分暴露,并与活性位点结合,抑制PBP2a的酶活性。这种双重作用机制增强了头孢洛林对MRSA的抗菌活性,使其成为一把针对MRSA的利器。但早在头孢洛林上市(2010年,美国食品和药物监督管理局批准上市)前的1998年,就已发现高水平耐头孢洛林MRSA。人们意识到头孢洛林并不能一劳永逸地解决MRSA,需要更深层次地探究二者之间作用机制,以更好运用好头孢洛林这一武器,延缓MRSA对其广泛耐药的时间。Methicillin-resistant Staphylococcus aureus (MRSA), a multidrug-resistant variant of S. aureus, was initially documented in the United Kingdom in 1961. Characterized by its elevated morbidity, mortality rates, and resistance to multiple antibiotic classes, MRSA rapidly emerged as a major global health threat following its discovery. The molecular basis of its broad-spectrum β-lactam resistance is attributed to the penicillin-binding protein 2a (PBP2a), encoded by the mecA gene. Ceftaroline fosamil, a fifth-generation cephalosporin approved by the U.S. Food and Drug Administration (FDA) in 2010, demonstrates exceptional antibacterial efficacy against MRSA through a unique dual mechanism involving both allosteric modulation and active site inhibition. By binding to the allosteric domain of PBP2a, ceftaroline induces conformational changes that expose the catalytic pocket, enabling subsequent interaction with the active site to irreversibly block its transpeptidase activity—a critical enzyme for bacterial cell wall biosynthesis. This dual-targeting strategy significantly enhances the compound’s bactericidal potency, establishing it as a cornerstone therapy for MRSA infections. Paradoxically, surveillance studies revealed the existence of high-level ceftaroline-resistant MRSA strains as early as 1998, predating the drug’s clinical approval by over a decade. These observations underscore the limitations of relying solely on ceftaroline as a definitive solution for MRSA management. The premature emergence of resistance necessitates a deeper investigation into the dynamic molecular interactions between ceftaroline and its bacterial targets, particularly the structural plasticity of PBP2a and compensatory mutations in auxiliary resistance determinants. Elucidating these mechanisms at atomic resolution is imperative for optimizing therapeutic regimens, designing next-generation β-lactams, and ultimately delaying the trajectory toward pan-resistance in MRSA populations.
文摘Background The Alere PBP2a SA Culture Colony Test is an FDA-cleared in vitro immunochromatographic assay for rapid detection of penicillin-binding protein2a(PBP2a)in Staphylococcus aureus.Methods We investigated the performance of the PBP2a SA Culture Colony Test with 78 coagulase-negative Staphylococcus(CoNS)isolates from different body sites,with the Vitek 2 Antimicrobial Susceptibility Test(AST)as a reference standard.Results The CoNS species were 62 S.epidermidis;6 S.lugdenensis;3 S.hominis;2 S.capitis;2 S.haemolyticus;and 1 each of S.simulans,S.auricularis,and S.warneri.Of the 78 CoNS isolates,68 showed concordance in the PBP2a IC assay and Vitek 2 AST.Discordance was seen for 10 S.epidermidis isolates,which showed negative in the PBP2a assay,despite oxacillin-resistance detection using the Vitek 2 AST(66.7%sensitivity and 100%specificity).All non-S.epidermidis CoNS were identified with 100%concordance using the PBP2a IC assay and Vitek 2 AST.Conclusion We demonstrated that,while the PBP2a IC assay has low sensitivity in determining the susceptibility of S.epidermidis to oxacillin,it highly accurately predicted the susceptibility of non-S.epidermidis CoNS to oxacillin.The diagnostic accuracy for non-S.epidermidis CoNS needs further assessment with more isolates to confirm our findings.
