Strategic approaches to overcome resistance against Gram negative pathogens using β-lactamase inhibitors and β-lactam enhancers: The activity of three novel diazabicyclooctanes, WCK 5153, zidebactam (WCK 5107), and WCK 4234 (original) (raw)
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Antimicrobial Agents and Chemotherapy
PER β-lactamases are an emerging family of extended-spectrum β-lactamases (ESBL) found in Gram-negative bacteria. PER β-lactamases are unique among class A enzymes as they possess an inverted omega (Ω) loop and extended B3 β-strand. These singular structural features are hypothesized to contribute to their hydrolytic profile against oxyimino-cephalosporins (e.g., cefotaxime and ceftazidime). Here, we tested the ability of avibactam (AVI), a novel non-β-lactam β-lactamase inhibitor to inactivate PER-2. Interestingly, the PER-2 inhibition constants (i.e., k 2 / K = 2 × 10 3 ± 0.1 × 10 3 M −1 s −1 , where k 2 is the rate constant for acylation (carbamylation) and K is the equilibrium constant) that were obtained when AVI was tested were reminiscent of values observed testing the inhibition by AVI of class C and D β-lactamases (i.e., k 2 / K range of ≈10 3 M −1 s −1 ) and not class A β-lactamases (i.e., k 2 / K range, 10 4 to 10 5 M −1 s −1 ). Once AVI was bound, a stable complex with P...
Antimicrobial agents and chemotherapy, 2017
Zidebactam and WCK 5153 are novel β-lactam enhancers that are bicyclo-acyl hydrazides (BCH), derivatives of diazabicyclooctane (DBO) scaffold, targeted for the treatment of serious infections caused by highly drug-resistant Gram-negative pathogens. In this report, we determined the PBP inhibition profiles and the antimicrobial activity of zidebactam and WCK 5153 against P. aeruginosa, including multidrug-resistant (MDR) metallo-β-lactamase (MBL)-producing high-risk clones. MICs and time-kill assays were conducted for zidebactam, WCK 5153 and antipseudomonal β-lactams using wild-type PAO1 strain, MexAB-OprM-hyperproducing (mexR), porin deficient (oprD) and AmpC-hyperproducing (dacB) derivatives of PAO1 and MBL-expressing clinical strains, ST175 (blaVIM-2) and ST111 (blaVIM-1). Furthermore, steady-state kinetics was used to assess the inhibitory potential of these compounds against the purified VIM-2 MBL. Zidebactam and WCK 5153 showed specific PBP2 inhibition and did not inhibit VIM-...
The increasingly worrisome situation of antimicrobial resistances has pushed synthetic chemists to design original molecules that can fight these resistances. To do so, inhibiting β-lactamases, one of the main modes of resistance to β-lactam antibiotics, is one of the most sought-after strategies, as recently evidenced by the development and approval of avibactam, relabactam and vaborbactam. Yet molecules able to inhibit simultaneously β-lactamases belonging to different molecular classes remain scarce and currently there is no metallo-β-lactamase inhibitor approved for clinical use. Having recently developed a synthetic methodology to access imino-analogues of β-lactams (Chem. – Eur. J. 2017, 23, 12991,see ref) we decided to evaluate them as potential β-lactamase inhibitors and specifically against carbapenemases, which can hydrolyze and inactivate penicillins, cephalosporins and carbapenems. Herein we eport our findings that show that our newly developed family of molecules are in...
Current Challenges in Antimicrobial Chemotherapy: Focus on β-Lactamase Inhibition
Drugs, 2010
The use of the three classical b-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam) in combination with b-lactam antibacterials is currently the most successful strategy to combat b-lactamase-mediated resistance. However, these inhibitors are efficient in inactivating only class A b-lactamases and the efficiency of the inhibitor/antibacterial combination can be compromised by several mechanisms, such as the production of naturally resistant class B or class D enzymes, the hyperproduction of AmpC or even the production of evolved inhibitor-resistant class A enzymes. Thus, there is an urgent need for the development of novel inhibitors. For serine active enzymes (classes A, C and D), derivatives of the b-lactam ring such as 6-b-halogenopenicillanates, b-lactam sulfones, penems and oxapenems, monobactams or trinems seem to be potential starting points to design efficient molecules (such as AM-112 and LK-157). Moreover, a promising nonb-lactam molecule, NXL-104, is now under clinical development. In contrast, an ideal inhibitor of metallo-b-lactamases (class B) remains to be found, despite the huge number of potential molecules already described (biphenyl tetrazoles, cysteinyl peptides, mercaptocarboxylates, succinic acid derivatives, etc.). The search for such an inhibitor is complicated by the absence of a covalent intermediate in their catalytic mechanisms and the fact that b-lactam derivatives often behave as substrates rather than as inhibitors. Currently, the most promising broad-spectrum inhibitors of class B enzymes are molecules presenting chelating groups (thiols, carboxylates, etc.) combined with an aromatic group.
Tetrahedron, 1989
Computational chemistry made possible the prediction of the three-dimensional structures of y-lactam analogues of penems and carbapenems before the analogues were made. Molecular superpositioning showed that these novel structures with a 7P-acylamino side-chain present the pharmacophoric groups in close spatial similarity to the groups in biologically active cephalosporin and penicillin antibiotics. This suggests that 8-oxo-7-acylamino-1-azabicyclo[3.3.0]act-2-ene-2-carboxylates and the 4-thia-analogues can be accommodated in the same active sites of essential bacterial penicillin-bmding proteins where cephalosporins and penicilliis am recognized. The syntheses of these compounds am reported. The y-lactams exhibit low, but detectable levels of antibacterial activity and suggest promise that substantial activity can be achieved with other y-lactams. NOCH3 ATM0 = Co 22a: RI = NH3,
Antimicrobial Agents and Chemotherapy, 2019
Impeding, as well as reducing, the burden of antimicrobial resistance in Gram-negative pathogens is an urgent public health endeavor. Our current antibiotic armamentarium is dwindling, while major resistance determinants (e.g., extended-spectrum β-lactamases [ESBLs]) continue to evolve and disseminate around the world. One approach to attack this problem is to develop novel therapies that will protect our current agents. AAI101 is a novel penicillanic acid sulfone β-lactamase inhibitor similar in structure to tazobactam, with one important difference. AAI101 possesses a strategically placed methyl group that gives the inhibitor a net neutral charge, enhancing bacterial cell penetration. AAI101 paired with cefepime, also a zwitterion, is in phase III of clinical development for the treatment of serious Gram-negative infections. Here, AAI101 was found to restore the activity of cefepime against class A ESBLs (e.g., CTX-M-15) and demonstrated increased potency compared to that of piper...
Antimicrobial Agents and Chemotherapy, 2017
Multidrug-resistant Acinetobacter baumannii has rapidly spread worldwide, resulting in a serious threat to hospitalized patients. Zidebactam and WCK 5153 are novel non-β-lactam bicyclo-acyl hydrazide β-lactam enhancer antibiotics being developed to target multidrug-resistant A. baumannii . The objectives of this work were to determine the 50% inhibitory concentrations (IC 50 s) for penicillin-binding proteins (PBP), the OXA-23 inhibition profiles, and the antimicrobial activities of zidebactam and WCK 5153, alone and in combination with β-lactams, against multidrug-resistant A. baumannii . MICs and time-kill kinetics were determined for an A. baumannii clinical strain producing the carbapenemase OXA-23 and belonging to the widespread European clone II of sequence type 2 (ST2). Inhibition of the purified OXA-23 enzyme by zidebactam, WCK 5153, and comparators was assessed. All of the compounds tested displayed apparent K i values of >100 μM, indicating poor OXA-23 β-lactamase inhib...
Synthesis and biological evaluation of novel β-lactam-metallo β-lactamase inhibitors
RSC Advances, 2023
b-lactamases are enzymes that deactivate b-lactam antibiotics through a hydrolysis mechanism. There are two known types of b-lactamases: serine b-lactamases (SBLs) and metallo b-lactamases (MBLs). The two existing strategies to overcome b-lactamase-mediated resistance are (a) to develop novel b-lactam antibiotics that are not susceptible to hydrolysis by these enzymes; or (b) to develop b-lactamase inhibitors that deactivate the enzyme and thereby restore the efficacy of the co-administered antibiotics. Many commercially available SBL inhibitors are used in combination therapy with antibiotics to treat antimicrobial resistant infections; however, there are only a handful of MBL inhibitors undergoing clinical trials. In this study, we present 11 novel potential MBL inhibitors (via multi-step chemical synthesis), that have shown to completely restore the efficacy of meropenem (#2 mg L −1) against New Delhi metallo-b-lactamase (NDM) producing Klebsiella pneumoniae in vitro. These compounds contain a cyclic amino acid zinc chelator conjugated to various commercially available b-lactam antibiotic scaffolds with the aim to improve the overall drug transport, lipophilicity, and pharmacokinetic/pharmacodynamic properties as compared to the chelator alone. Biological evaluation of compounds 24b and 24c has further highlighted the downstream application of these MBLs, since they are non-toxic at the selected doses. Time-kill assays indicate that compounds 24b and 24c exhibit sterilizing activity towards NDM producing Klebsiella pneumoniae in vitro using minimal concentrations of meropenem. Furthermore, 24b and 24c proved to be promising inhibitors of VIM-2 (K i = 0.85 and 1.87, respectively). This study has revealed a novel series of b-lactam MBLIs that are potent, efficacious, and safe leads with the potential to develop into therapeutic MBLIs. cantly to antibiotic resistance. 1,3,4 The Antimicrobial Resistance (AMR) National Strategy Framework (2018-2024), as well as the Global Research and Development priority setting for AMR, and the Global Antibiotic Research and Development Partnership, prioritise research regarding antimicrobial treatment to help prevent obsolete antibiotics emanating as a result of mutations and bacterial evolution. 5-7 Antibiotic resistance has worsened, due to the empirical treatment of hospitalised COVID-19 patients. 3,8,9 There are several initiatives in place to either raise awareness, help reduce, or keep track of resistance, such as: the Global Action Plan on Antimicrobial Resistance (GAP); World Antimicrobial Awareness Week (WAAW); The Global Antimicrobial Resistance and Use Surveillance System (GLASS); Global Research and Development priority setting for AMR; Access Watch Reserve (AWaRe); and Global Antibiotic Research and Development Partnership (GARDP). 7 Murray et al. estimated that 4.95 million deaths occurred in the year 2019 as a result of antibiotic resistance. 6 Identied Klebsiella pneumoniae, as a common pathogen accounting for 29% of all reported bacterial infections. 7 Klebsiella pneumoniae has recently been identied as a bacteria of concern, as mentioned in several reports, studies, and reviews, and is further substantiated by the resistance map (Fig. 1) generated from the CDDEP (Centre for Disease Dynamics, Economics and Policy). 10 Unfortunately,
Science Archives
Bacterial resistance is spreading internationally and poses a serious threat to humans. β-lactam resistance has enhanced to an uncontrolled rate due to many reasons. The most significant form of resistance is destruction of the ß-lactam ring by a bacterial enzyme named ß-lactamase enzyme which is essential for antibacterial activity. There are currently six β-lactamases inhibitors that can be used clinically in conjugation with the antibiotic in order to protect them from enzymatic attacks. They bind the β-lactamase enzyme thus the β-lactam antibiotic catches the transpeptidase (PBP) which has the responsibility of peptidoglycan synthesis and disables it thus causing cell wall lysis. However, in order to tackle the fast escalating ß-lactam resistance, additional research is needed in order to create novel drugs with broad-spectrum. Herein we represent the recently published works of the β-lactamases inhibitors. Until nowadays there are no clinically approved MBL inhibitors, Efforts ...