# Inducible Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus

> **NIH NIH R01** · UNIVERSITY OF NOTRE DAME · 2020 · $518,582

## Abstract

Project Summary/Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic human bacterial pathogen, which is
broadly resistant to β-lactam antibiotics. This resistance is inducible and is conferred by a set of genes that
encode an antibiotic sensor/signal transducer protein, a gene repressor and two resistance determinants (a
class A β-lactamases and a unique penicillin-binding protein (PBP) designated as PBP2a). Covalent binding of
the β-lactam antibiotic to the surface domain of the sensor/signal transducer protein initiates the induction of
resistance, which entails biochemical events on the cytoplasmic side involving proteolysis of the gene
repressor and transcription of the genes for the antibiotic-resistance determinants. We address the sequence
of events that take place in the cytoplasm in this grant application. We propose in Specific Aim 1 to study two
responses that MRSA experiences after the recognition of the antibiotic on the surface. One is a fragmentation
of the BlaR1 (the sensor/transducer protein) in its cytoplasmic protease domain, which is believed to activate it
(i.e., bring it out of latency). Another is phosphorylation of a protein that we refer to as BlaR2. We propose to
document that proteolysis of the cytoplasmic domain initiates the onset of induction. Phosphorylation of BlaR2
also ensues antibiotic recognition on the surface and is essential for the antibiotic response. We propose to
identify and characterize BlaR2 and determine the site of its phosphorylation in elucidating a functional link
between activation of BlaR1 and phosphorylation of BlaR2. In Specific Aim 2, we would like to build on our
preliminary findings on inhibitors of BlaR2 phosphorylation in identification of molecules that could serve as
potentiators of β-lactam antibiotics. This class of compounds prevents BlaR2 phosphorylation, which we have
documented to result in sensitization of the organism to β-lactam antibiotics. Such a class of molecules has the
potential of bring back β-lactam antibiotics from obsolescence in treatment of MRSA infections. MRSA has
been with humanity for over 50 years. These studies will shed definitive light on the complex machinery that
MRSA strains have evolved for resistance to β-lactam antibiotics.

## Key facts

- **NIH application ID:** 9841876
- **Project number:** 5R01AI104987-08
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Shahriar Mobashery
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $518,582
- **Award type:** 5
- **Project period:** 2013-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841876

## Citation

> US National Institutes of Health, RePORTER application 9841876, Inducible Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus (5R01AI104987-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9841876. Licensed CC0.

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