A Novel CMY Variant Confers Transferable High-Level Resistance to Ceftazidime-Avibactam in Multidrug-Resistant Escherichiacoli

Zhou, Junxin; Wang, Weiping; Liang, Min; Yu, Qian; Cai, Sheng; Lei, Tailong; Jiang, Yan; Du, Xiaoxing; Zhou, Zongtan; Yu, Yunsong

doi:10.1128/spectrum.03349-22

Cited by 6 publications

(3 citation statements)

References 47 publications

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“…A similar expansion of the substrate binding site is observed in AmpC Ent385 , which contains the deletion of residues A294 and P295 and also confers reduced susceptibility to cefiderocol ( 6 , 15 ). In addition, CMY-172 and CMY-178 contain the deletion of three residues K290, V291, and A292 on the R2 loop, resulting in the higher MICs of 16 and 64 mg/L for ceftazidime-avibactam, respectively, and 1 mg/L for cefiderocol ( 30 ). Moreover, our results indicated that the CMY-2-like β-lactamases strongly recognize cefiderocol compared to the other β-lactamases.…”

Section: Discussionmentioning

confidence: 99%

Structural insights into the molecular mechanism of high-level ceftazidime–avibactam resistance conferred by CMY-185

Kawai,

Shropshire,

Suzuki

et al. 2024

mBio

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β-Lactamases can accumulate stepwise mutations that increase their resistance profiles to the latest β-lactam agents. CMY-185 is a CMY-2-like β-lactamase and was identified in an Escherichia coli clinical strain isolated from a patient who underwent treatment with ceftazidime-avibactam. CMY-185, possessing four amino acid substitutions of A114E, Q120K, V211S, and N346Y relative to CMY-2, confers high-level ceftazidime-avibactam resistance, and accumulation of the substitutions incrementally enhances the level of resistance to this agent. However, the functional role of each substitution and their interplay in enabling ceftazidime-avibactam resistance remains unknown. Through biochemical and structural analysis, we present the molecular basis for the enhanced ceftazidime hydrolysis and impaired avibactam inhibition conferred by CMY-185. The substituted Y346 residue is a major driver of the functional evolution as it rejects primary avibactam binding due to the steric hindrance and augments oxyimino-cephalosporin hydrolysis through a drastic structural change, rotating the side chain of Y346 and then disrupting the H-10 helix structure. The other substituted residues E114 and K120 incrementally contribute to rejection of avibactam inhibition, while S211 stimulates the turnover rate of the oxyimino-cephalosporin hydrolysis. These findings indicate that the N346Y substitution is capable of simultaneously expanding the spectrum of activity against some of the latest β-lactam agents with altered bulky side chains and rejecting the binding of β-lactamase inhibitors. However, substitution of additional residues may be required for CMY enzymes to achieve enhanced affinity or turnover rate of the β-lactam agents leading to clinically relevant levels of resistance. IMPORTANCE Ceftazidime-avibactam has a broad spectrum of activity against multidrug-resistant Gram-negative bacteria including carbapenem-resistant Enterobacterales including strains with or without production of serine carbapenemases. After its launch, emergence of ceftazidime-avibactam-resistant strains that produce mutated β-lactamases capable of efficiently hydrolyzing ceftazidime or impairing avibactam inhibition are increasingly reported. Furthermore, cross-resistance towards cefiderocol, the latest cephalosporin in clinical use, has been observed in some instances. Here, we clearly demonstrate the functional role of the substituted residues in CMY-185, a four amino-acid variant of CMY-2 identified in a patient treated with ceftazidime-avibactam, for high-level resistance to this agent and low-level resistance to cefiderocol. These findings provide structural insights into how β-lactamases may incrementally alter their structures to escape multiple advanced β-lactam agents.

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Section: Discussionmentioning

confidence: 99%

Structural insights into the molecular mechanism of high-level ceftazidime–avibactam resistance conferred by CMY-185

Kawai,

Shropshire,

Suzuki

et al. 2024

mBio

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“…According to Zhou et al, is a new CMY variation that mediates high-level resistance to ceftazidime-avibactam by improving ceftazidime hydrolysis and decreasing avibactam affinity. Notably, high-frequency horizontal transmission of bla CMY-178 was possible without incurring fitness costs (Zhou et al, 2023). In addition, a recent study by Hernańdez-Garcıá et al found that strains of E. coli with the KPC-49 variant were resistant to ceftazidime/avibactam.…”

Section: Ceftazidime-avibactammentioning

confidence: 99%

A review of the mechanisms that confer antibiotic resistance in pathotypes of E. coli

Nasrollahian,

Graham,

Halaji

2024

Front. Cell. Infect. Microbiol.

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The dissemination of antibiotic resistance in Escherichia coli poses a significant threat to public health worldwide. This review provides a comprehensive update on the diverse mechanisms employed by E. coli in developing resistance to antibiotics. We primarily focus on pathotypes of E. coli (e.g., uropathogenic E. coli) and investigate the genetic determinants and molecular pathways that confer resistance, shedding light on both well-characterized and recently discovered mechanisms. The most prevalent mechanism continues to be the acquisition of resistance genes through horizontal gene transfer, facilitated by mobile genetic elements such as plasmids and transposons. We discuss the role of extended-spectrum β-lactamases (ESBLs) and carbapenemases in conferring resistance to β-lactam antibiotics, which remain vital in clinical practice. The review covers the key resistant mechanisms, including: 1) Efflux pumps and porin mutations that mediate resistance to a broad spectrum of antibiotics, including fluoroquinolones and aminoglycosides; 2) adaptive strategies employed by E. coli, including biofilm formation, persister cell formation, and the activation of stress response systems, to withstand antibiotic pressure; and 3) the role of regulatory systems in coordinating resistance mechanisms, providing insights into potential targets for therapeutic interventions. Understanding the intricate network of antibiotic resistance mechanisms in E. coli is crucial for the development of effective strategies to combat this growing public health crisis. By clarifying these mechanisms, we aim to pave the way for the design of innovative therapeutic approaches and the implementation of prudent antibiotic stewardship practices to preserve the efficacy of current antibiotics and ensure a sustainable future for healthcare.

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“…Recent studies have demonstrated antibiotic resistance against combination therapies involving the latest BLIs and against new β-lactams, such as durlobactam [28], relebactam [29,30], zidebactam [31], tazobactam [32], taniborbactam [33], thiol-containing BLIs under development [34], and cefiderocol [35]. The resistance mechanisms include upregulation of efflux, mutations in the β-lactam target PBPs, and expression of β-lactamases and mutants less susceptible to the specific BLI, such as KPC-109 [36], NDM-9 [33], IMP-6 [34], and CMY-178 [37]. These resistance mutants highlight the need for the antimicrobial field to constantly explore novel inhibitor chemotypes to counter future resistance.…”

Section: Targeting β-Lactamases: Innovative Technologies and Promisin...mentioning

confidence: 99%

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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A Novel CMY Variant Confers Transferable High-Level Resistance to Ceftazidime-Avibactam in Multidrug-Resistant Escherichiacoli

Cited by 6 publications

References 47 publications

Structural insights into the molecular mechanism of high-level ceftazidime–avibactam resistance conferred by CMY-185

Structural insights into the molecular mechanism of high-level ceftazidime–avibactam resistance conferred by CMY-185

A review of the mechanisms that confer antibiotic resistance in pathotypes of E. coli

Drug Discovery in the Field of β-Lactams: An Academic Perspective

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