# Understanding B-Lactam Resistance in Acinetobacter baumannii

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $385,768

## Abstract

The WHO lists Acinetobacter baumannii (Ab) as the most problematic pathogen infecting patients. In this
renewal, we will build upon our successful accomplishments in our first two R01s in which we developed an
entirely new class of boronic acid transition state inhibitors (BATSIs), explored the structure activity relationships
(SAR) of the chromosomal cephalosporinase of Ab, ADC-7, as well as the class D carbapenemases OXA-23, -
24/40 and -66/51, and defined the efflux pumps governing antibiotic resistance. Herein, we will embark upon
innovative ways to overcome β-lactam resistance by proposing two novel approaches. Firstly, we propose that
structural and mechanistic similarities exist between class C and D β-lactamases present in Acinetobacter spp.
that reveal a common intermediate. This notion will drive efforts to synthesize carbapenem and cephem based
BATSIs that will inactivate both β-lactamase classes. Secondly, we advance that chromosomal blaADC and blaOXA
overexpression in resistant isolates creates new cellular vulnerabilities that can be identified by genetic
approaches such as Tn-Seq. These unique vulnerabilities will be exploited in high-throughput screens (HTS) to
identify novel compounds that specifically target highly β-lactam resistant isolates. The novel targets and new
inhibitors identified could lead to the “next generation” of therapeutics that overcome high-level β-lactam resistant
Ab and avoid the indiscriminate killing of all bacteria. To meet these goals, we will build upon our insights into
the structures of ADC and OXA β-lactamases and the chemistry of α-triazoles and amide bioisostere BATSIs to
explore the SAR of these two series of compounds that will identify inhibitory activity toward both class C and D
β-lactamases. As carbapenems are known to be both substrate (class D) and inhibitors (class C) of these β-
lactamases, we will first synthesize novel BATSI compounds based upon a carbapenem backbone, as this
scaffold provides a common core from which to build a broad-spectrum inhibitor of both C and D β-lactamases.
These new inhibitors will be evaluated microbiologically, biochemically, and structurally against emerging clinical
variants of ADC and OXA β-lactamases. We will then validate the selected inhibitors against a panel of clinical
strains. Simultaneously, we will also use Tn-Seq to identify mutations that confer a synthetic lethal phenotype in
an Ab strain overexpressing the chromosomal blaADC or blaOXA β-lactamase. A genetic screen will be performed
to confirm that the genes identified confer a synthetic lethal phenotype. Lastly, we will utilize high throughput
screening (HTS) to identify new therapeutic agents that impact the interplay of chromosomal blaADC or blaOXA
expression and bacterial viability. The current prevalence of MDR and pan-resistant strains of Ab, combined with
the lack of new antibiotics, underscores the critical need for the development of novel therapeutics to combat
this bacterium. Our g...

## Key facts

- **NIH application ID:** 10241454
- **Project number:** 5R01AI072219-13
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** ROBERT A. BONOMO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,768
- **Award type:** 5
- **Project period:** 2007-08-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241454

## Citation

> US National Institutes of Health, RePORTER application 10241454, Understanding B-Lactam Resistance in Acinetobacter baumannii (5R01AI072219-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241454. Licensed CC0.

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