Drug development concerning metallo-β-lactamases in gram-negative bacteria

Liu, Xiuyun; Zhao, Jing; Zhang, Bin; Duan, Xuexia; Jen, Jin; Wu, Weiwei; Zhou, Yüxia; Wang, Hefeng

doi:10.3389/fmicb.2022.959107

Cited by 10 publications

(5 citation statements)

References 125 publications

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“…Reference BMD was performed to determine the activity of 3 investigational antibiotics that are not currently available clinically (ie, cefepime-taniborbactam, cefepime-zidebactam, and meropenem-xeroborbactam). These 3 agents were specifically tested as preclinical studies indicate that they have a relatively high likelihood of activity against NDM-producing bacterial isolates [ 24 ]. For all AST studies, quality control organisms were prepared weekly or each day of testing, as appropriate.…”

Section: Methodsmentioning

confidence: 99%

An NDM-Producing Escherichia coli Clinical Isolate Exhibiting Resistance to Cefiderocol and the Combination of Ceftazidime-Avibactam and Aztreonam: Another Step Toward Pan-β-Lactam Resistance

Simner

Bergman

Conzemius

et al. 2023

Open Forum Infectious Diseases

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Background Cefiderocol and ceftazidime-avibactam plus aztreonam (CZA-ATM) are preferred treatment regimens for NDM-producing infections. Methods We report the case of a United States patient who traveled to India to receive a renal transplant. He subsequently experienced pyelonephritis by an NDM-producing Escherichia coli. Broth microdilution and the broth disk elution method indicated resistance to all β-lactams, including cefiderocol and CZA-ATM. WGS investigations were undertaken to identify resistance mechanisms. Results An E. coli isolate belonging to sequence type (ST) 167 containing a blaNDM-5 gene was identified on a plasmid of the IncFIA/IncFIB/IncFIC replicon groups. When compared to the genome of another ST167 E. coli clinical isolate containing blaNDM-5 and exhibiting susceptibility to cefiderocol and CZA-ATM, a 12 base pair insertion in ftsI, translating to a four amino acid duplication in PBP3 was identified. Moreover, a blaCMY-59 gene was harbored on an IncI-γ replicon type and frameshift mutations were identified in the cirA iron transport gene. Conclusions This is the first clinical case of a United States patient harboring an NDM-producing isolate exhibiting resistance to all available β-lactam agents. The isolate’s unexpected resistance to cefiderocol and CZA-ATM was likely due to a combination of (1) a modified PBP3 (increased MICs to both regimens), (2) truncated iron-binding protein (increased cefiderocol MIC), and (3) a blaCMY gene (reduced CZA-ATM activity). E. coli ST167 clinical isolates harboring blaNDM-5 genes are a recognized international high-risk clone. When coupled with the additional mechanisms identified in our patient’s isolate, which is not uncommon for this high-risk clone, pan-β-lactam resistance may occur.

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Section: Methodsmentioning

confidence: 99%

An NDM-Producing Escherichia coli Clinical Isolate Exhibiting Resistance to Cefiderocol and the Combination of Ceftazidime-Avibactam and Aztreonam: Another Step Toward Pan-β-Lactam Resistance

Simner

Bergman

Conzemius

et al. 2023

Open Forum Infectious Diseases

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“…Here, we highlight some representative compounds. Whereas classical β-lactamase inhibitors, such as clavulanate, were active only against class A enzymes, the latest drug discovery efforts have focused on MBL inhibitors [103] and cross-class activity compounds [104], including those active against multiple classes of SBLs or even all classes (Figure 3). These novel inhibitor chemotypes have led to new combination therapies targeting β-lactam resistance and a better understanding of β-lactamase activity.…”

Section: Novel β-Lactamase Inhibitor Scaffoldsmentioning

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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“…resistance to nearly all existing β-lactam antibiotics and the unavailability of clinically useful drug regimens for MBLs [27,47,48]. To date, there are no clinically available inhibitors for MBLs.…”

Section: Plos Onementioning

confidence: 99%

Inhibition of β-lactamase function by de novo designed peptide

Mishra,

Cosic,

Loncarevic

et al. 2023

PLoS ONE

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Antimicrobial resistance is a great public health concern that is now described as a “silent pandemic”. The global burden of antimicrobial resistance requires new antibacterial treatments, especially for the most challenging multidrug-resistant bacteria. There are various mechanisms by which bacteria develop antimicrobial resistance including expression of β-lactamase enzymes, overexpression of efflux pumps, reduced cell permeability through downregulation of porins required for β-lactam entry, or modifications in penicillin-binding proteins. Inactivation of the β-lactam antibiotics by β-lactamase enzymes is the most common mechanism of bacterial resistance to these agents. Although several effective small-molecule inhibitors of β-lactamases such as clavulanic acid and avibactam are clinically available, they act only on selected class A, C, and some class D enzymes. Currently, none of the clinically approved inhibitors can effectively inhibit Class B metallo-β-lactamases. Additionally, there is increased resistance to these inhibitors reported in several bacteria. The objective of this study is to use the Resonant Recognition Model (RRM), as a novel strategy to inhibit/modulate specific antimicrobial resistance targets. The RRM is a bio-physical approach that analyzes the distribution of energies of free electrons and posits that there is a significant correlation between the spectra of this energy distribution and related protein biological activity. In this study, we have used the RRM concept to evaluate the structure-function properties of a group of 22 β-lactamase proteins and designed 30-mer peptides with the desired RRM spectral periodicities (frequencies) to function as β-lactamase inhibitors. In contrast to the controls, our results indicate 100% inhibition of the class A β-lactamases from Escherichia coli and Enterobacter cloacae. Taken together, the RRM model can likely be utilized as a promising approach to design β-lactamase inhibitors for any specific class. This may open a new direction to combat antimicrobial resistance.

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Drug development concerning metallo-β-lactamases in gram-negative bacteria

Cited by 10 publications

References 125 publications

An NDM-Producing Escherichia coli Clinical Isolate Exhibiting Resistance to Cefiderocol and the Combination of Ceftazidime-Avibactam and Aztreonam: Another Step Toward Pan-β-Lactam Resistance

An NDM-Producing Escherichia coli Clinical Isolate Exhibiting Resistance to Cefiderocol and the Combination of Ceftazidime-Avibactam and Aztreonam: Another Step Toward Pan-β-Lactam Resistance

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

Inhibition of β-lactamase function by de novo designed peptide

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