# Determining the value of PBP 7/8 as an antimicrobial target for XDR-A. baumannnii

> **NIH VA I01** · VA WESTERN NEW YORK HEALTHCARE SYSTEM · 2022 · —

## Abstract

Anticipated Impacts on Veterans Health Care. The incidence of infections due to highly resistant
Acinetobacter baumannii is increasing. True pan drug resistant (PDR) strains have been reported.
Unfortunately, the newly approved antimicrobials ceftolozane-tazobactam, ceftazidime-avibactam, and
meropenem/vaborbactam are poorly active against resistant A. baumannii. The need to identify new
antimicrobials active against A. baumannii is pressing.
Background. We have demonstrated that the A. baumannii low molecular mass (LMM) penicillin binding
protein 7/8 (PBP 7/8) is essential in vivo (i.e., required for bacterial survival in a host) in rat pneumonia and
subcutaneous abscess infection models, and is required for survival in human serum and ascites. Our initial
studies on PBP 7/8 were performed in an antimicrobial sensitive strain AB307-0294. These findings have
since been confirmed with the extensively drug resistant (XDR) strain HUMC1. Since our initial observation
other investigators, using INseq and Tn-seq, have shown that PBP 7/8 is needed for A. baumannii survival in
the Galleria mellonella insect infection model and serum respectively. PBP 7/8 has many characteristics that
support its potential as a high value drug target. However, based on studies in rich laboratory medium, LMM
PBPs including PBP 7/8 have been perceived to be non-essential. As a result, PBP 7/8 have received scant
attention as an antibacterial target and has not been considered for A. baumannii. However, our data
contradicts this paradigm and endorses the need for additional studies on PBP 7/8 in XDR A. baumannii.
Therefore, our objective is to validate PBP 7/8 as a drug target, delineate mechanisms that mediate its ex
vivo and in vivo essentiality, and to identify compounds that inactivate PBP 7/8.
Objectives and Methods. To achieve these objectives, studies on PBP 7/8 will be extended to include
additional XDR strains of A. baumannii to confirm our findings are generalizable (aim 1). Aim 1 also will also
explore mechanisms by which PBP 7/8 enables growth/survival of A. baumannii ex vivo and in vivo and
identify the innate host defense factors it protects against. Increasing data support the need to treat infections
due to XDR isolates with multiple agents, thereby increasing efficacy and protecting against the development
of resistance. Our demonstration that the loss of PBP 7/8 production increases susceptibility to complement
and lysozyme mediated bactericidal activity and changes cell structure supports the hypothesis that the
inability to produce PBP 7/8 affects permeability, a critical factor in the intrinsic antimicrobial resistance of A.
baumannii. Therefore, an additional goal of this proposal will be to assess the whether the loss of PBP 7/8
production enhances the activity of adjunctive therapy with antimicrobials and/or monoclonal antibodies
directed against the capsule (aim 2). Additional studies in aim 2 will assess whether the loss of PBP 7/8 affects
the produ...

## Key facts

- **NIH application ID:** 10406232
- **Project number:** 5I01BX004677-03
- **Recipient organization:** VA WESTERN NEW YORK HEALTHCARE SYSTEM
- **Principal Investigator:** THOMAS A RUSSO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406232

## Citation

> US National Institutes of Health, RePORTER application 10406232, Determining the value of PBP 7/8 as an antimicrobial target for XDR-A. baumannnii (5I01BX004677-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10406232. Licensed CC0.

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