Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes
June 30, 2021
Robert E. Trout, Allison Zulli, Eugen Mesaros, Randy W. Jackson, Steven Boyd, Bin Liu, Jodie Hamrick, Denis Daigle, Cassandra L. Chatwin, Kaitlyn John, Lisa McLaughlin, Susan M. Cusick, William J. Weiss, Mark E. Pulse, Daniel C. Pevear, Greg Moeck, Luigi Xerri, and Christopher J. Burns
A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant “superbugs” has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
Microbiological characterization of VNRX-5236: a broad spectrum β-lactamase inhibitor for rescue of the orally bioavailable cephalosporin ceftibuten as a carbapenem-sparing agent against strains of Enterobacterales expressing extended spectrum β-lactamases and serine carbapenemases.
May 7, 2021
Cassandra L. Chatwin, Jodie C. Hamrick, Robert E. L. Trout, Cullen L. Myers, Susan M. Cusick, William J. Weiss, Mark E. Pulse, , Luigi Xerri, Christopher J. Burns, Gregory Moeck, Denis M. Daigle, Kaitlyn John, Tsuyoshi Uehara, and Daniel C. Pevear
There is an urgent need for oral agents to combat resistant gram-negative pathogens. Here we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI) and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended spectrum β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 104 M−1. sec−1, and prolonged active site residence times (t1/2, 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 μg/mL) in isogenic strains of E. coli expressing class A, C or D β-lactamases demonstrated an expanded spectrum of activity relative to oral comparators including investigational penems, sulopenem and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC90 = 0.25 μg/mL), KPCs (MIC90 = 1 μg/mL), class C cephalosporinases (MIC90 = 1 μg/mL) and OXA-48-type carbapenemases (MIC90 = 1 μg/mL). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination. In vivo, whereas ceftibuten alone was ineffective (ED50, >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by K. pneumoniae producing KPC carbapenemase (ED50, 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales.
Activity of Cefepime in Combination with the Novel β-Lactamase Inhibitor Taniborbactam (VNRX-5133) against Extended-Spectrum-β-Lactamase-Producing Isolates in In Vitro Checkerboard Assays
March 18, 2021
Wendy Kloezen, Ria J. Melchers, Panagiota-Christina Georgiou, Johan W. Mouton, Joseph Meletiadis
Extended-spectrum-β-lactamase (ESBL)-producing strains are increasing worldwide, limiting therapeutic options. Taniborbactam (VNRX-5133) is a newly developed β-lactamase inhibitor with a wide spectrum of activity covering both serine and metallo enzymes. We therefore evaluated cefepime-taniborbactam activity against ESBL-producing isolates and determined the concentrations to be used in MIC determinations in the clinical laboratory. The in vitro activity of cefepime (0.06 to 256 mg liter−1) combined with taniborbactam (0.03 to 32 mg liter−1) against 129 clinically and molecularly well-documented ESBL-producing isolates (42 Escherichia coli, 39 Klebsiella pneumoniae, 28 Pseudomonas aeruginosa, 16 Enterobacter cloacae, 2 Citrobacter freundii, and 2 Enterobacter aerogenes) was tested with a broth microdilution checkerboard method based on the ISO standard. The MICs of cefepime alone and in combination, together with percentage resistance at different concentrations of taniborbactam, were calculated for each species and resistance mechanism. The median (range)/MIC90 of cefepime was 32 (0.125 to 256)/256 mg liter−1 for all Enterobacterales isolates (n = 101), with 72% being resistant, and 32 (8 to 256)/128 mg liter−1 for the 28 P. aeruginosa isolates, with 86% being resistant. The median (range)/90th percentile concentration of taniborbactam required to restore Enterobacterales susceptibility to cefepime (MIC ≤1 mg liter−1) was 0.06 (≤0.03 to 32)/4 mg liter−1 and P. aeruginosa susceptibility to increased exposure to cefepime (MIC ≤8 mg liter−1) 1 (≤0.032 to 32)/32 mg liter−1. At a fixed concentration of 4 mg liter−1 of taniborbactam, cefepime median (range)/MIC90 were reduced to 0.125 (0.06 to 4)/1 mg liter−1 for Enterobacterales with no resistant isolates found, and to 8 (2 to 64)/16 mg liter−1 for P. aeruginosa isolates, where 36% remained resistant. The combination cefepime-taniborbactam demonstrated a potent activity against ESBL isolates, restoring susceptibility of all Enterobacterales and two-thirds of P. aeruginosa isolates.
Pharmacodynamics of Ceftibuten: An Assessment of an Oral Cephalosporin against Enterobacterales in a Neutropenic Murine Thigh Model
February 19, 2021
Maxwell J. Lasko, Tomefa E. Asempa, David P. Nicolau
Efforts to develop and pair novel oral β-lactamase inhibitors with existing β-lactam agents to treat extended spectrum β-lactamase (ESBL) and carbapenemase-producing Enterobacterales are gaining ground. Ceftibuten is an oral third-generation cephalosporin capable of achieving high urine concentrations; however, there are no robust data describing its pharmacodynamic profile. This study characterizes ceftibuten pharmacokinetics and pharmacodynamics in a neutropenic murine thigh infection model. Enterobacterales isolates expressing no known clinically-relevant enzymatic resistance (n = 7) or harboring an ESBL (n = 2) were evaluated. The ceftibuten minimum inhibitory concentrations (MICs) were 0.03–4 mg/L. Nine ceftibuten regimens, including a human-simulated regimen (HSR) equivalent to clinical ceftibuten doses of 300 mg taken orally every 8 h, were utilized to achieve various fT > MICs. A sigmoidal Emax model was fitted to fT > MIC vs. change in log10 CFU/thigh to determine the requirements for net stasis and 1-log10 CFU/thigh bacterial burden reduction. The growth of the 0 h and 24 h control groups was 5.97 ± 0.37 and 8.51 ± 0.84 log10 CFU/thigh, respectively. Ceftibuten HSR resulted in a -0.49 to -1.43 log10 CFU/thigh bacterial burden reduction at 24 h across the isolates. Stasis and 1-log10 CFU/thigh reduction were achieved with a fT > MIC of 39% and 67%, respectively. The fT > MIC targets identified can be used to guide ceftibuten dosage selection to optimize the likelihood of clinical efficacy.
Potent inhibitory activity of taniborbactam towards NDM-1 and NDM-1Q119X mutants, and in vitro activity of cefepime/taniborbactam against MBLs producing Enterobacterales
November 24, 2020
Alessandra Piccirilli, Bernardetta Segatore, Fabrizia Brisdelli, Gianfranco Amicosante, Mariagrazia Perilli
This study aimed to investigate the in vitro activity of taniborbactam (VNRX-5133), a novel broad-spectrum bicyclic boronate, against NDM-1 and Q119E, Q119K, Q119C, Q119F, Q119V, and Q119Y NDM-1 variants, which showed an increased activity towards some β-lactams, including cefepime.
Inhibition kinetic assays were spectrophotometrically performed using cefepime (50 μM) as the reporter substrate and 80 nM of each enzyme. Taniborbactam behaves as a competitive inhibitor towards NDM-1 and NDM-1 Q119 variants with lower Ki values (range 3–16 nM). The phenotypic profile was assessed inn both Enterobacterales clinical isolates and engineered Escherichia coli BL21(DE3) strains by conventional broth microdilution procedures according to the Clinical and Laboratory Standards Institute (CLSI).
Taniborbactam at a fixed concentration of 4 mg/L was able to restore activity of cefepime in 24 of 26 Enterobacterales clinical isolates harbouring metallo-β-lactamases with MIC50/MIC90 values of 14 mg/L. Cefepime MICs were drastically reduced in all clinical isolates and in NDM-1 and Q119X producing Escherichia coli BL21(DE3). Taniborbactam was unable to restore susceptibility to cefepime in two IMP variants producing clinical isolates.
The inhibition level of NDM enzymes provided by taniborbactam protects the antibacterial activity of cefepime from this important metallo-β-lactamase.
Oral cephalosporin and β-lactamase inhibitor combinations for ESBL-producing Enterobacteriaceae urinary tract infections
October 28, 2020
Adam G. Stewart, Patrick N. A. Harris, Andrew Henderson, Mark A. Schembri and David L. Paterson
Activity of beta-lactam/taniborbactam (VNRX-5133) combinations against carbapenem-resistant Gram-negative bacteria
October 9, 2020
Shazad Mushtaq, Anna Vickers, Michel Doumith, Matthew J Ellington, Neil Woodford, David M Livermore
Boronates are of growing interest as beta-lactamase inhibitors. The only marketed analogue, vaborbactam, principally targets KPC carbapenemases, but taniborbactam (VNRX-5133, Venatorx) has a broader spectrum.
MICs of cefepime and meropenem were determined combined with taniborbactam or avibactam for carbapenem-resistant UK isolates. beta-Lactamase genes and porin alterations were sought by PCR or sequencing.
Taniborbactam potentiated partner beta-lactams against: (i) Enterobacterales with KPC, other class A, OXA-48-like, VIM and NDM (not IMP) carbapenemases; and (ii) Enterobacterales inferred to have combinations of ESBL or AmpC activity and impermeability. Potentiation of cefepime (the partner for clinical development) by taniborbactam was slightly weaker than by avibactam for Enterobacterales with KPC or OXA-48-like carbapenemases, but MICs of cefepime-taniborbactam were similar to those of ceftazidime/avibactam, and the spectrum was wider. MICs of cefepime-taniborbactam nonetheless remained >8 + 4 mg/L for 22%–32% of NDM-producing Enterobacterales. Correlates of raised cefepime-taniborbactam MICs among these NDM Enterobacterales were a cefepime MIC >128 mg/L, particular STs and, for Escherichia coli only: (i) the particular blaNDM variant (even though published data suggest all variants are inhibited similarly); (ii) inserts in PBP3; and (iii) raised aztreonam-avibactam MICs. Little or no potentiation of cefepime or meropenem was seen for Pseudomonas aeruginosa and Acinetobacter baumannii with MBLs, probably reflecting slower uptake or stronger efflux. Potentiation of cefepime was seen for Stenotrophomonas maltophilia and Elizabethkingia meningoseptica, which have both chromosomal ESBLs and MBLs.
Taniborbactam broadly reversed cefepime or meropenem non-susceptibility in Enterobacterales and, less reliably, in non-fermenters.
Metallo-Beta-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline
September 21, 2020
Sara E. Boyd, David M. Livermore, David C. Hooper, William W. Hope
Modern medicine is threatened by the global rise of antibiotic resistance, especially among Gram-negative bacteria. Metallo-beta-lactamase (MBL) enzymes are a particular concern and are increasingly disseminated worldwide, though particularly in Asia. Many MBL producers have multiple further drug resistances, leaving few obvious treatment options. Nonetheless, and more encouragingly, MBLs may be less effective agents of carbapenem resistance in vivo, under zinc limitation, than in vitro. Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development. They evade all recently licensed beta-lactam–beta-lactamase inhibitor combinations, although several stable agents and inhibitor combinations are at various stages in the development pipeline. These potential therapies, along with the epidemiology of producers and current treatment options, are the focus of this review.
In vivo pharmacodynamics of new-generation beta-lactamase inhibitor taniborbactam (formerly VNRX-5133) in combination with cefepime against serine-beta-lactamase-producing Gram-negative bacteria
August 30, 2020
Kamilia Abdelraouf, Safa Almarzoky Abuhussain, David P Nicolau
Cefepimeitaniborbactam is a cephalosporin/cyclic boronate beta-lactamase inhibitor combination under development for the treatment of infections due to MDR Enterobacterales and Pseudomonas aeruginosa. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic index, relative to taniborbactam exposure, that correlated most closely with the efficacy of the cefepime-taniborbactam combination and the magnitude of index required for efficacy against serine-beta-lactamase-producing strains.
Twenty-six clinical Enterobacterales (expressing ESBLs, plasmid-mediated AmpC and/or carbapenemases of classes A or D; cefepime/taniborbactam combination MICs 0.06-16 mg/L) and 11 clinical P. aeruginosa (AmpC overproducing or KPC expressing; cefepime-taniborbactam combination MICs 1-16 mg/L) were evaluated. A cefepime human-simulated regimen (HSR) equivalent to a clinical dose of 2 g q8h as a 2 h infusion was given in combination with taniborbactam for 24 h. For a subset of P. aeruginosa isolates, a sub-therapeutic cefepime exposure was utilized.
Dose-fractionation studies revealed that dosing frequency had no impact on taniborbactam potentiation of cefepime activity. Relative to the initial bacterial burden, the median taniborbactam fAUC0-24/MIC associated with 1 log kill in combination with the cefepime HSR for Enterobacterales and P. aeruginosa isolates was 2.62 and 0.46, respectively. In combination with sub-therapeutic cefepime, the median taniborbactam fAUC0-24/MIC associated with 1 and 2 log kill against AmpC-overproducing P. aeruginosa was 2.00 and 3.30, respectively, relative to the bacterial burden in the cefepime-treated groups. The taniborbactam HSR (equivalent to 0.5 g q8h as a 2 h infusion) was adequate to attain ≥1 log reduction against all test isolates.
Our data show that the cefepime-taniborbactam combination (2 g/0.5 g q8h as a 2 h infusion) exerts potent in vivo activity against cefepime-resistant isolates, including serine-carbapenemase producers.
In vitro activity of the novel beta-lactamase inhibitor taniborbactam (VNRX-5133), in combination with cefepime or meropenem, against MDR Gram-negative bacterial isolates from China
July 15, 2020
Xiaojuan Wang, Chunjiang Zhao, Qi Wang, Zhanwei Wang, Xinyue Liang, Feifei Zhang, Yawei Zhang, Han Meng, Hongbin Chen, Shuguang Li, Chengcheng Zhou, Henan Li, Hui Wang
To evaluate in vitro activity of the novel beta-lactamase boronate inhibitor taniborbactam (VNRX-5133) combined with cefepime or meropenem against 500 urinary Gram-negative bacilli.
Cefepime-taniborbactam and 14 comparators were tested by broth microdilution or agar dilution methods. A total of 450 Enterobacteriaceae and 50 Pseudomonas aeruginosa were selected from 2017 to 2019 based on different β-lactamase-producing or resistance phenotypes. For carbapenem-non-susceptible isolates, the modified carbapenem inactivation method (mCIM), EDTA-CIM (eCIM) and amplification of carbapenemase genes were performed. For NDM-producing isolates and those with cefepime-taniborbactam MICs >8 mg/L, the MICs of meropenem-taniborbactam and/or mutations in PBP3 were investigated.
Taniborbactam improved cefepime activity with the same efficiency as avibactam improved ceftazidime activity against 66 KPC-2 producers, 30 non-carbapenemase-producing carbapenem-non-susceptible Enterobacteriaceae and 28 meropenem-susceptible P. aeruginosa. However, cefepime-taniborbactam exhibited more potent activity than ceftazidime-avibactam against 56 ESBL-producing, 61 AmpC-producing, 32 ESBL and AmpC co-producing, 87 NDM-producing and 21 MBL-producing Enterobacteriaceae predicted by phenotypic mCIM and eCIM, 82 Enterobacteriaceae that were susceptible to all tested beta-lactams and 22 carbapenem-non-susceptible P. aeruginosa. A four-amino acid ‘INYR’ or ‘YRIN’ insertion, with or without a one/two-amino acid mutation in PBP3, may have caused cefepime-taniborbactam MICs >8 mg/L among 96.6% (28/29) of the NDM-5-producing Escherichia coli, which accounted for the majority of isolates with cefepime-taniborbactam MICs >8 mg/L (76.1%, 35/46).
Taniborbactam’s superior breadth of activity, when paired with cefepime or meropenem, suggests these beta-lactam/beta-lactamase inhibitor combinations could be promising candidates for treating urinary tract infections caused by ESBL and/or AmpC, KPC or NDM-producing Enterobacteriaceae or P. aeruginosa.
VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-Beta-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa
December 23, 2019
Jodie C. Hamrick, Jean-Denis Docquier, Tsuyoshi Uehara, Cullen L. Myers, David A. Six, Cassandra L. Chatwin, Kaitlyn J. John, Salvador F. Vernacchio, Susan M. Cusick, Robert E.L. Trout, Cecilia Pozzi, Filomena De Luca, Manuela Benvenuti, Stefano Mangani, Bin Liu, Randy W. Jackson, Greg Moeck, Luigi Xerri, Christopher J. Burns, Daniel C. Pevear, Denis M. Daigle
As shifts in the epidemiology of beta-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved beta-lactam (BL)–beta-lactamase inhibitor (BLI) combinations address widespread serine beta-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-beta-lactamases (KPC, OXA-48) or clinically important metallo-beta-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by beta-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki) values ranging from 0.019 to 0.081 μM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4 μg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.
Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-Beta-Lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections
November 25, 2019
Bin Liu, Robert E. Lee Trout, Guo-Hua Chu, Daniel McGarry, Randy W. Jackson, Jodie C. Hamrick, Denis M. Daigle, Susan M. Cusick, Cecilia Pozzi, Filomena De Luca, Manuela Benvenuti, Stefano Mangani, Jean-Denis Docquier, William J. Weiss, Daniel C. Pevear, Luigi Xerri, Christopher J. Burns
A major resistance mechanism in Gram-negative bacteria is the production of beta-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent beta-lactamases can now confer resistance to other beta-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of beta-lactamase-producing multi-drug-resistant “superbugs” has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-beta-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum beta-lactamase inhibitor. In vitro and in vivo studies demonstrated that restored the activity of beta-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.
Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases
August 27, 2019
The bicyclic boronate VNRX-5133 (taniborbactam) is a new type of β-lactamase inhibitor in clinical development. We report that VNRX-5133 inhibits serine-β-lactamases (SBLs) and some clinically important metallo-β-lactamases (MBLs), including NDM-1 and VIM-1/2. VNRX-5133 activity against IMP-1 and tested B2/B3 MBLs was lower/not observed. Crystallography reveals how VNRX-5133 binds to the class D SBL OXA-10 and MBL NDM-1. The crystallographic results highlight the ability of bicyclic boronates to inhibit SBLs and MBLs via binding of a tetrahedral (sp3) boron species. The structures imply conserved binding of the bicyclic core with SBLs/MBLs. With NDM-1, by crystallography, we observed an unanticipated VNRX-5133 binding mode involving cyclization of its acylamino oxygen onto the boron of the bicyclic core. Different side-chain binding modes for bicyclic boronates for SBLs and MBLs imply scope for side-chain optimization. The results further support the “high-energy-intermediate” analogue approach for broad-spectrum β-lactamase inhibitor development and highlight the ability of boron inhibitors to interchange between different hybridization states/binding modes.
Interplay between beta-lactamases and new beta-lactamase inhibitors
March 5, 2019
Karen Bush, Patricia A Bradford
Resistance to beta-lactam antibiotics in Gram-negative bacteria is commonly associated with production of beta-lactamases, including extended-spectrum beta-lactamases (ESBLs) and carbapenemases belonging to different molecular classes: those with a catalytically active serine and those with at least one active-site Zn2+ to facilitate hydrolysis. To counteract the hydrolytic activity of these enzymes, combinations of a beta-lactam with a beta-lactamase inhibitor (BLI) have been clinically successful. However, some β-lactam-BLI combinations have lost their effectiveness against prevalent Gram-negative pathogens that produce ESBLs, carbapenemases or multiple beta-lactamases in the same organism. In this Review, descriptions are provided for medically relevant β-lactamase families and various BLI combinations that have been developed or are under development. Recently approved inhibitor combinations include the inhibitors avibactam and vaborbactam of the diazabicyclooctanone and boronic acid inhibitor classes, respectively, as new scaffolds for future inhibitor design.