# Understanding B-Lactam Resistance in Acinetobacter baumannii

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $574,870

## Abstract

The Centers for Disease Control and Prevention (CDC) designated Carbapenem-Resistant Acinetobacter
baumannii (CRAb) an “urgent threat pathogen” for which novel therapies are desperately needed. The current
COVID-19 pandemic has only accelerated the emergence of CRAb in medical intensive care units and hospitals,
creating a parallel health care crisis in the US. The combination of β-lactamase production and cell penetration
challenge every drug class used to treat CRAb. By applying novel chemistry to design more potent “cross-class”
boronic acid transition state inhibitors (BATSIs) that are effective β-lactamase inactivators, and developing a
deeper understanding of the genetic diversity of β-lactamases present in CRAb, we propose to extend our efforts
to also target class B metallo-β-lactamases (MBLs; specifically IMP-1, -14, and NDM-1, as they are the most
prevalent MBLs in Ab), and develop drugs that penetrate Ab more readily. We will build upon the efficacy of two
potent BATSIs (MB076 and CR167 that were iteratively designed in our current funding cycle) to also interact
with Zn2+ ions in the active site of MBLs, as well as penetrate CRAb more effectively. Concurrently, we discovered
that OXA β-lactamase overexpression in Ab drives significant collateral changes in bacteria consistent with
increased amidase activity. As a result, peptidoglycan integrity is impacted, and new cellular vulnerabilities were
revealed. Further studies have also shown that at least five genes become conditionally essential in OXA
expressing Ab. As a result, we propose a multidisciplinary approach to overcome CRAb using the following
strategies. Firstly, we propose that structural and mechanistic similarities in class B, C, and D β-lactamases can
be exploited to permit the design of “cross-class” inhibitors by the addition of novel functional groups (e.g., Zinc
Binding groups, ZBGs). In addition, we will design novel cyclic boronates that demonstrate interactions in the
active site that inhibit MBLs as well as serine β-lactamases. Secondly, we hypothesize that the penetration of
BATSIs into Ab can be improved and overcome by modifications of the R1/R2 side chains to enhance steric and
electronic interactions that facilitate passage through porins, specifically CarO. In addition, we will synthesize
novel BATSIs that use Fe3+ mediated transport that penetrate CRAb readily and resist efflux. We will perform
molecular modeling and structural analyses of CarO to give us insight on how to overcome this major porin
conferring imipenem resistance. Studying the mechanistic/structural features inherent to CarO and the imipenem
scaffold will facilitate our first two goals. Thirdly, we discovered that OXA β-lactamase expression in CRAb
creates new cellular vulnerabilities and that certain gene products become essential for viability, but only in OXA-
overexpressing isolates. We propose that these gene products represent novel bacterial targets that can be
inhibited by small molec...

## Key facts

- **NIH application ID:** 10879565
- **Project number:** 2R01AI072219-15A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** ROBERT A. BONOMO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $574,870
- **Award type:** 2
- **Project period:** 2007-08-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879565

## Citation

> US National Institutes of Health, RePORTER application 10879565, Understanding B-Lactam Resistance in Acinetobacter baumannii (2R01AI072219-15A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879565. Licensed CC0.

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