# Novel inhibitors of bacterial cell envelope biogenesis for prophylaxis against carbapenem-resistant Enterobacteriaceae

> **NIH NIH U19** · HACKENSACK UNIVERSITY MEDICAL CENTER · 2021 · $558,902

## Abstract

Abstract
In 2017, the WHO designated carbapenem-resistant Enterobacteriaceae (CRE) a Priority 1 “critical superbug”.
As few therapies remain to treat CRE, the risk of “pan-resistant” CRE untreatable by any currently available
antibiotic also exists, and entirely new agents with novel mechanisms of action (MOA) not cross-resistant to
SOC agents languish. We believe that in addition to new strategies to treat CRE infections, greater
consideration should also be given to preventing CRE infections from occurring in the first place. Our proposal
aims to develop an O-antigen (O-a) biosynthetic inhibitory agent that potentiates serum-mediated killing (SMK)
and is efficacious in prophylactic CRE rodent models of infection. We have shown that the O-a biosynthesis
gene wecA, a nonessential gene under standard growth conditions, is essential for growth and pathogenesis in
the presence of mammalian serum. Our proposal outlines a plan to develop synthetic inhibitors of WecA that
we previously discovered and optimized to inhibit the Gram-positive WecA ortholog, TarO. Our Aims are:
Aim 1. MOA validation and assay development. Demonstrate tarocins directly target WecA to elicit SMK
effects. Establish target engagement (TE) and pathway engagement (PE) screening assays. Build isogenic set
of permeability and efflux deficient mutants in E. coli (Ec), K. pneumoniae (Kp), P. aeruginosa (Pa), and A.
baumannii (Ab) to guide med chem SAR. Milestone (M) 1. Identify up to 4 chemically distinct tarocin
subseries for progression to Lead ID with > 4-fold EC50 shift in SMK by WecA overexpression, dose-
dependent depletion of O-a, and causal drugR mutations mapping to wecA.
Aim 2. Lead Identification. Drive SAR efforts to achieve WT activity by empirically assaying for SMK against a
panel of Ec/Kp/Pa/Ab permeability and efflux deficient mutants, employing the emerging ‘Hergenrother
physicochemical rules of GN entry’, and exploring the utility of siderophore conjugation. M2. Identify up to 2
distinct tarocin subseries for progression to Lead Opt with Ec and Kp WT activity (Human Serum (HS)-MIC
< 16 ug/ml), exposure to cover HS-MIC for 4 hrs, Ec TE and PE selectivity, Ec and Kp FOR < 1 x 10-9 at 8X HS-
MIC, > 90% mammalian cell viability at 10 X HS-MIC, and HS-MIC90 < 64 ug/ml (n=50 isolates).
Aim 3. Lead Optimization. Optimize PK, drug-like properties, and in vitro activity. M3. Identify 3 tarocin
analogs for progression to Aim 4 with Ec/Kp WT activity (HS-MIC < 1 ug/ml), exposure to cover HS-MIC 8
hrs, Ec TE and PE selectivity, Ec/Kp FOR £ 1x 10-9 at 4X HS-MIC, >90% HepG2/HEK293 cell viability at 10X
HS-MIC, clean CYP/ion channels (>10 uM), PanLabs IC50 > 10 uM, and HS-MIC90 £ 2 ug/ml (n=100 isolates).
Aim 4. In vivo efficacy demonstration. Demonstrate efficacy with up to three lead optimized compounds in
rodent prophylaxis models of CRE bacteremia and thigh infections. M4. Identify 1 tarocin analog as a pre-
clinical prophylaxis candidate that demonstrates > 3 log reduction o...

## Key facts

- **NIH application ID:** 10138987
- **Project number:** 5U19AI142731-03
- **Recipient organization:** HACKENSACK UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Terry Roemer
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $558,902
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138987

## Citation

> US National Institutes of Health, RePORTER application 10138987, Novel inhibitors of bacterial cell envelope biogenesis for prophylaxis against carbapenem-resistant Enterobacteriaceae (5U19AI142731-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10138987. Licensed CC0.

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