Bacterial Resistance to β‐Lactam Antibiotics: Compelling Opportunism, Compelling Opportunity

Fisher, Jed F.; Meroueh, Samy O.; Mobashery, Shahriar

doi:10.1002/chin.200524267

Cited by 201 publications

(342 citation statements)

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“…A major difference between penem 1 and meropenem compared to clavulanate, sulbactam, and tazobactam is the presence of a double bond between the C 2 and C 3 positions in the former compounds. As previously shown, this sp 2 configuration plays a major role in the binding/catalysis of penems (clavulanate included) and carbapenems (2,21,37,38). Sulbactam and tazobactam, which possess an sp 3 hybridized R 2 side chain, are positioned in a different manner in the active site.…”

Section: Vol 55 2011 Ctx-m-9 Inhibition By ␤-Lactamase Inhibitors 3469mentioning

confidence: 94%

“…Sulbactam and tazobactam, which possess an sp 3 hybridized R 2 side chain, are positioned in a different manner in the active site. In addition, the presence of the leaving group at the C 6 position also influences reaction chemistry (carbapenems versus penem 1 versus clavulanate) (21). To demonstrate the above findings as they pertain to the hybridization at the C 2 position, we generated a model of meropenem and penem 1 in the active site.…”

Section: Vol 55 2011 Ctx-m-9 Inhibition By ␤-Lactamase Inhibitors 3469mentioning

confidence: 99%

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Exploring the Inhibition of CTX-M-9 by β-Lactamase Inhibitors and Carbapenems

Bethel

Taracila

Shyr

et al. 2011

Antimicrob Agents Chemother

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Currently, CTX-M ␤-lactamases are among the most prevalent and most heterogeneous extended-spectrum ␤-lactamases (ESBLs). In general, CTX-M enzymes are susceptible to inhibition by ␤-lactamase inhibitors. However, it is unknown if the pathway to inhibition by ␤-lactamase inhibitors for CTX-M ESBLs is similar to TEM and SHV ␤-lactamases and why bacteria possessing only CTX-M ESBLs are so susceptible to carbapenems. Here, we have performed a kinetic analysis and timed electrospray ionization mass spectrometry (ESI-MS) studies to reveal the intermediates of inhibition of CTX-M-9, an ESBL representative of this family of enzymes. CTX-M-9 ␤-lactamase was inactivated by sulbactam, tazobactam, clavulanate, meropenem, doripenem, ertapenem, and a 6-methylidene penem, penem 1. CTX-M enzymes are becoming one of the most prevalent extended-spectrum ␤-lactamases (ESBLs) (3,8,9,(30)(31)(32) in the world. The widespread dissemination of CTX-M ␤-lactamases, especially Escherichia coli ST131 possessing CTX-M-15, has had a significant impact on the treatment of hospital-and community-acquired infections caused by E. coli and other enteric bacilli (6, 7, 13, 23, 36, 41, 44-49, 55, 59).As class A family ␤-lactamases, CTX-Ms are the most genetically heterogeneous (5 major divisions, CTX-M-1, -2, -8, -25, and -9-like groups) (1, 24, 35, 44-46, 58, 60). Most CTX-M enzymes expressed in E. coli provide a high level of resistance to the oxyimino-cephalosporins, cefotaxime and ceftriaxone, and variable levels of resistance to cefepime and cefpirome (3,43). Depending on the type of CTX-M expressed by the isolates, the MICs of ceftazidime are also increased (43). In addition, the MICs of combinations of clavulanate with amoxicillin or ticarcillin vary, and in some cases, low-level resistance has been observed (3).As a consequence of their clinical importance, the reaction mechanism of CTX-M ESBLs has been the subject of intense study (10-12, 14, 16, 42). However, the molecular properties and characteristics of CTX-M that determine the level of susceptibility and resistance to ␤-lactam-␤-lactamase inhibitor combinations and carbapenems are still unknown. Of the currently available inhibitors, tazobactam is the most active (50% inhibitory concentrations [IC 50 s] are 2 to 10 nM for tazobactam and 9 to 90 nM for clavulanate), and sulbactam is the least active (IC 50 s are 0.1 to 4.5 M) (3).In order to develop more effective and broader-spectrum ␤-lactamase inhibitors (18), detailed kinetic and biochemical measurements are needed to reveal the important intermediates in the inactivation of the CTX-M family. In TEM-1 and SHV-1, Arg244 is important in the mechanism of inactivation of carbapenems (imipenem and meropenem), clavulanic acid, sulbactam, and tazobactam (27,28,51,53,63). CTX-M-9 does not contain Arg244, and mutagenesis of a potential corresponding position, Arg276, does not firmly establish this amino acid as an "Arg244 equivalent" (42). Given the differences among class A enzymes, we wondered what the intermediates of inactivation by ...

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Section: Vol 55 2011 Ctx-m-9 Inhibition By ␤-Lactamase Inhibitors 3469mentioning

confidence: 94%

Section: Vol 55 2011 Ctx-m-9 Inhibition By ␤-Lactamase Inhibitors 3469mentioning

confidence: 99%

Exploring the Inhibition of CTX-M-9 by β-Lactamase Inhibitors and Carbapenems

Bethel

Taracila

Shyr

et al. 2011

Antimicrob Agents Chemother

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“…However, the dissemination of ␤-lactamases, hydrolytic enzymes that inactivate ␤-lactams through cleavage of the amide bond of the ␤-lactam ring, is threatening their clinical longevity (3)(4)(5). Production of ␤-lactamases has become the most common ␤-lactam resistance mechanism in bacteria, particularly in opportunistic Gram-negative species.…”

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confidence: 99%

Crystal Structures of Pseudomonas aeruginosa GIM-1: Active-Site Plasticity in Metallo-β-Lactamases

Borra

Samuelsen

Spencer

et al. 2013

Antimicrob Agents Chemother

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Metallo-␤-lactamases (MBLs) have rapidly disseminated worldwide among clinically important Gram-negative bacteria and have challenged the therapeutic use of ␤-lactam antibiotics, particularly carbapenems. The bla GIM-1 gene, encoding one such enzyme, was first discovered in a Pseudomonas aeruginosa isolate from 2002 and has more recently been reported in Enterobacteriaceae. Here, we present crystal structures of GIM-1 in the apo-zinc (metal-free), mono-zinc (where Cys221 was found to be oxidized), and di-zinc forms, providing nine independently refined views of the enzyme. GIM-1 is distinguished from related MBLs in possessing a narrower active-site groove defined by aromatic side chains (Trp228 and Tyr233) at positions normally occupied by hydrophilic residues in other MBLs. Our structures reveal considerable flexibility in two loops (loop 1, residues 60 to 66; loop 2, residues 223 to 242) adjacent to the active site, with open and closed conformations defined by alternative hydrogen-bonding patterns involving Trp228. We suggest that this capacity for rearrangement permits GIM-1 to hydrolyze a wide range of ␤-lactams in spite of possessing a more constrained active site. Our results highlight the structural diversity within the MBL enzyme family.

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“…Pela análise do perfil de susceptibilidade aos betalactâmicos associados a inibidores de betalactamases, observa-se que a maioria das linhagens resistentes aos primeiros provavelmente é produtora de betalactamases, o que representa um grande problema na nossa realidade hoje. Além disso, a resistência simultânea de algumas linhagens aos betalactâmicos associados a inibidores de betalactamases permite sugerir que haja resistência por outros mecanismos 6 . Observou-se também resistência às cefalosporinas, como a ceftazidima, em linhagens de bastonetes Gram negativos não-fermentadores.…”

Section: Discussionunclassified

Ocorrência de bactérias clinicamente relevantes nos resíduos de serviços de saúde em um aterro sanitário brasileiro e perfil de susceptibilidade a antimicrobianos

Nascimento

Januzzi

Leonel

et al. 2009

Rev. Soc. Bras. Med. Trop.

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Entre os diferentes tipos de resíduos gerados pelo homem, os produzidos nos serviços de saúde têm merecido maior atenção nos últimos anos, principalmente devido às suas frações infectantes. Devido à grande variedade de fontes geradoras de resíduos, a ABSTRACTHealth service waste gives rise to controversy regarding its importance for human, animal and environmental health. Occurrences of clinically relevant bacteria in piles of health service waste in a sanitary landfill and their antimicrobial susceptibility profile were evaluated. Aliquots of leachate were processed for selective isolation of Staphylococcus sp, Gram-negative rods of the Enterobacteriaceae family and non-fermenters. Bacterial resistance to all the antimicrobials tested was observed in all microbial groups, including resistance to more than one drug. The results make it possible to suggest that viable bacteria in health service waste represent risks to human and animal health. Furthermore, occurrences of multiresistant strains support the hypothesis that health service waste acts as a reservoir for resistance markers, with an environmental impact. The lack of regional legislation concerning segregation, treatment and final disposal of waste may expose different populations to risks of transmission of infectious diseases associated with multiresistant microorganisms.

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Bacterial Resistance to β‐Lactam Antibiotics: Compelling Opportunism, Compelling Opportunity

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 201 publications

References 1 publication

Exploring the Inhibition of CTX-M-9 by β-Lactamase Inhibitors and Carbapenems

Exploring the Inhibition of CTX-M-9 by β-Lactamase Inhibitors and Carbapenems

Crystal Structures of Pseudomonas aeruginosa GIM-1: Active-Site Plasticity in Metallo-β-Lactamases

Ocorrência de bactérias clinicamente relevantes nos resíduos de serviços de saúde em um aterro sanitário brasileiro e perfil de susceptibilidade a antimicrobianos

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