# Bicarbonate-Mediated Enhancement of Beta-Lactam-MRSA Killing: Mechanisms and Clinical Translatability

> **NIH NIH R01** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2021 · $437,644

## Abstract

ABSTRACT
 Methicillin-resistant Staphylococcus aureus (MRSA) are a leading cause of invasive infections in both
community-acquired and hospital-associated contexts. MRSA strains are intrinsically resistant by standard
in vitro susceptibility testing to β-lactam antibiotics. In contrast, methicillin-susceptible S. aureus (MSSA)
strains remain highly susceptible to many standard-of-care β-lactams (e.g. oxacillin; nafcillin; cefazolin).
 β-lactams are not recommended for treating MRSA infections: i) MRSA β-lactam MICs are above
current CLSI “breakpoints”; ii) they bind relatively poorly to penicillin-binding protein (PBP) 2a (predominant
PBP in MRSA strains responsible for cell wall synthesis and division); iii) β-lactam levels required to saturate
PBP 2a exceed human serum levels achieved with standard clinical dose-regimens; and iv) treatment of
experimental MRSA infections (e.g., endocarditis) with β-lactams are generally ineffective.
 Several labs recently showed that bicarbonate supplemention of standard MIC testing media can
“sensitize” some (but not all) MRSA strains in vitro to β-lactams and host defense peptides (e.g., LL-37 from
neutrophils; skin). Further, MRSA strains exhibiting a “bicarbonate- responsive” phenotype in vitro (i.e.,
β-lactam-resistant in standard media, but susceptible in bicarbonate-containing media) were effectively
eradicated in murine bacteremia models with selected β-lactams. We amplified these observations using four
prototype MRSA strains (LAC-USA-300; COL [USA 100] ; MW-2 [USA 400]; BMC1001 [USA 300] which
demonstrated the following key outcomes: i) all strains were resistant in vitro in standard (MHB) to both
oxacillin (OX) and cefazolin (CFZ); two strains exhibited a bicarbonate-responsive phenotype in bicarbonate-
supplemented MHB, becoming highly susceptible to both β-lactams, while two did not; ii) two bicarbonate-
responsive strains were heterotypic on population analyses, while the other two strains were homotypic (AUCs
> 0.9); iii) both bicarbonate-responsive strains were effectively cleared from all target organs by both OX and
CFZ in experimental endocarditis (IE), while two bicarbonate-nonresponsive strains were refractory to therapy;
and iv) bicarbonate impacted both the mecA-pbp2a and sarA-sigB genetic pathways.
 The current proposal will investigate: i) the scope of the bicarbonate-responsive phenotype in vitro to
β-lactams among a larger collection of clinical MRSA strains; ii) the overall large-scale translatability of such
in vitro metrics to a relevant in vivo model of invasive MRSA infection (IE); and iii) the mechanism(s) underlying
bicarbonate-responsiveness in MRSA. This proposal could lay the foundation for pivotal clinical trial(s)
assessing predictability of modified in vitro testing of MRSA to β-lactams, utilizing bicarbonate
supplementation of standard media. This research has the overarching potential to fundamentally transform
current MRSA in vitro susceptibility testing methods for β-...

## Key facts

- **NIH application ID:** 10173623
- **Project number:** 5R01AI146078-03
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** ARNOLD S BAYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $437,644
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10173623

## Citation

> US National Institutes of Health, RePORTER application 10173623, Bicarbonate-Mediated Enhancement of Beta-Lactam-MRSA Killing: Mechanisms and Clinical Translatability (5R01AI146078-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10173623. Licensed CC0.

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