# Development of New Antibiotics Against Multidrug-Resistant Staphylococcus aureus

> **NIH NIH R01** · RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL · 2020 · $391,347

## Abstract

Project Summary
Antibacterial resistance is an increasingly serious threat to global public health. In recognition of this threat,
the President’s Council of Advisors on Science and Technology (PCAST) has recently submitted a report to
President Obama underscoring the urgency of ensuring “an effective arsenal of antibiotics that is continuously
renewed.” Two pathogens recently identified by the CDC as major antibiotic resistance threats in the United
States are methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA).
This proposal is premised on the hypothesis that developing new antibiotics with novel mechanisms of action
will provide an innovative and effective therapy against MRSA and VRSA infections. The proposed project will
develop drugs that act against a new antibacterial target (FtsZ, a protein essential for bacterial cell division)
unexploited by any antibiotics in current clinical use. The proposal incorporates innovative solutions to
problems of drug administration, elimination, and resistance that have hindered early efforts to develop drugs
targeting bacterial cell division. Significantly, strong preliminary results are presented that provide validation
for the innovative approach. The three areas to be investigated in this project are:
1. Identification of compounds that improve antibiotic efficacy. A problem associated with FtsZ-targeting
 compounds that have been generated to date is rapid elimination due to metabolism. This aim is geared
 toward the synthesis and evaluation of new compounds designed for resistance to metabolism and thus
 longer durations of action and enhanced efficacy in vivo. The studies in this aim will include assays to
 establish that our compounds are sparing of human gut microflora, as well as human and other mammalian
cells.
2. Can other antibiotics function synergistically with our compounds? Synergistic combination therapy
 is an effective strategy for enhancing in vivo efficacy, while also minimizing the potential for toxicity and
 emergence of drug resistance. We hypothesize that our FtsZ-targeting compounds should act
 synergistically with drugs that target the penicillin binding proteins (PBPs), since both the PBPs and FtsZ
 play important roles in a common pathway leading to bacterial cell division. This aim is geared toward
 identifying PBP-targeting antibiotics that act synergistically in combination with our FtsZ-targeting
 compounds, while also reducing the frequency of resistance.
3. Selection of promising preclinical drug candidates. A critical step toward the selection of a preclinical
 candidate is a pharmacological safety assessment for potential toxicities. This aim is geared toward
 toxicological evaluation of our lead compounds with regard to genotoxicity (Ames mutagenicity),
 cardiotoxicity (hERG potassium channel inhibition), and single-dose acute toxicity.
Together, these investigations will culminate in the selection of preclinical drug candidat...

## Key facts

- **NIH application ID:** 9950977
- **Project number:** 5R01AI118874-05
- **Recipient organization:** RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
- **Principal Investigator:** Daniel S Pilch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,347
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950977

## Citation

> US National Institutes of Health, RePORTER application 9950977, Development of New Antibiotics Against Multidrug-Resistant Staphylococcus aureus (5R01AI118874-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9950977. Licensed CC0.

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