# Oral Metallo-Beta-Lactamase Inhibitors: Exploiting Reaction Mechanisms

> **NIH VA I01** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2021 · —

## Abstract

Gram-negative pathogens producing metallo-β-lactamases, MBLs, are a significant threat to our public health
as treatment options against bacteria possessing these resistance determinants are extremely limited. In
general, MBLs are the most worrisome carbapenemases, inactivating “last resort” β-lactams (e.g., imipenem
and meropenem) and resist all commercially available β-lactamase inhibitors (BLIs). The main challenge in
MBL inhibitor design is exploiting the reaction mechanism as it relates to the structural diversity of the 3 distinct
subclasses (B1, B2, and B3). Based on this approach, our consortium has successfully designed a series of
innovative compounds, bisthiazolidines (BTZs) and thiazolidines (TZs), inspired on a non-β-lactam
“penicillin core” decorated with specific metal binding groups. To date, BTZs and TZs are unique potent, non-
toxic, “cross-class” MBL inhibitors. Recently, we determined the structural basis of their inhibitory action, and
their microbiological activity (bactericidal when combined with a carbapenem). This inspires confidence in the
ability of BTZs and TZs to be effective against MBL producing Gram-negative bacteria. Interestingly, novel TZs
exhibit similar properties and potencies and in certain cases are superior to BTZs.
The overarching objectives of this project are to embark upon a “high risk-high reward” program in drug
discovery to develop an effective oral MBL inhibitor that is absorbed sufficiently from the gastrointestinal (GI)
tract and can be partnered with an oral carbapenem, tebipenem pivoxil (Tbp-Pvx). We are co-opting an
established strategy, the addition of a pivoxil group, which has been successful in at least two commercial
formulations (cefditoren pivoxil and tebipenem pivoxil) and adapting it to our developmental compounds (BTZs
and TZs). Since parenteral inhibitors for serine carbapenemases are already in clinical use (e.g., avibactam,
relebactam and vaborbactam) and only a few truly MBL inhibitors are in development (QPX7728 and
taniborbactam), our unique and specific formulation will address an unmet medical need, i.e. that of an oral
cross-subclass MBL inhibitor. By the nature of its components, Tbp-Pvx is also intended to be stable
against extended-spectrum β-lactamases (ESBLs) and class C cephalosporinases (AmpCs), which are
resistance determinants often present in MBL-producing strains. Additionally, we will mitigate the problems
associated with cephalosporins (resistance selection). As a lead compound, we have identified a potent BTZ (L
syn CS319) that effectively lowers MICs to within the susceptible range when paired with a carbapenem. As an
alternative, we have also synthesized potent TZ derivatives. We propose to develop the first oral
carbapenem and MBL inhibitor formulation to be considered for development that overcomes difficult to
treat carbapenem resistant infections mediated by MBLs. Our experimental evaluations stem from close
partnership with scientists in Argentina and Ur...

## Key facts

- **NIH application ID:** 10124877
- **Project number:** 1I01BX005307-01
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** ROBERT A. BONOMO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124877

## Citation

> US National Institutes of Health, RePORTER application 10124877, Oral Metallo-Beta-Lactamase Inhibitors: Exploiting Reaction Mechanisms (1I01BX005307-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124877. Licensed CC0.

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