# Resistance to Carbapenem Antibiotics in Acinetobacter baumannii

> **NIH NIH R01** · UNIVERSITY OF NOTRE DAME · 2020 · $673,906

## Abstract

ABSTRACT
Acinetobacter baumannii is listed by the CDC as a clinical pathogen that poses a serious antibiotic
resistance threat in the United States. A. baumannii is resistant to antimicrobial agents of different
classes, but the most troublesome is resistance to the last resort carbapenem antibiotics, which were
the drugs of choice for treatment of infections caused by this microorganism. The major mechanism of
resistance of A. baumannii to carbapenems is production of antibiotic-inactivating enzymes,
carbapenem-hydrolyzing class D β-lactamases or CHDLs. In addition, sensitivity of carbapenem
targets, bacterial penicillin-binding proteins (PBPs), rates of antibiotic penetration into the bacterial cell
and/or their expulsion by efflux pumps can also contribute to resistance. Levels of resistance to
carbapenem antibiotics reach up to 90% in some parts of the world, and mortality rates from infections
caused by such bacteria are staggeringly high, up to 50%. Our long-term goal is to develop novel
antibiotics for treatment of deadly A. baumannii infections. During the first cycle of funding for this grant
proposal, we performed in-depth characterization of clinically important CHDLs and proposed the
mechanism for their carbapenemase activity, which provides guidance for development of a new
generation of carbapenems capable of inhibiting these enzymes. The continuation of this research will
be a collaborative effort with Dr. John Buynak (co-PI) who developed dozens of novel atypically-
modified carbapenem antibiotics. We used these antibiotics to test our proposed mechanism for
deacylation and found three that inhibit the most prevalent A. baumannii CHDL, OXA-23, and possess
superior activity (when compared to commercial carbapenems) against OXA-23-producing A.
baumannii. Our proposed studies are aimed at in-depth characterization of these promising novel
drugs. We will determine activity of our compounds against A. baumannii strains expressing major
CHDLs and unveil kinetic and structural features responsible for their ability to inhibit these enzymes
(Aim 1). We will evaluate interaction of our novel carbapenems with their targets, PBPs, and determine
to what extent efflux pumps and porins influence bacterial resistance to these antibiotics (Aim 2).
Finally, we will design and characterize several dozen novel carbapenem antibiotics with the aim to
further improve their antimicrobial activity by enhancing their inhibitory potency against CHDLs,
improving affinity for PBPs and increasing penetration rates and resistance to efflux (Aim 3).

## Key facts

- **NIH application ID:** 9887256
- **Project number:** 2R01AI114668-06
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** JOHN D BUYNAK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $673,906
- **Award type:** 2
- **Project period:** 2015-08-01 → 2021-03-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9887256

## Citation

> US National Institutes of Health, RePORTER application 9887256, Resistance to Carbapenem Antibiotics in Acinetobacter baumannii (2R01AI114668-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9887256. Licensed CC0.

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