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

Award Number: R01AI146078
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG MRL	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	1/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	4/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $328,099 )
2023	2023	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	5	5/16/2023	NON-COMPETING CONTINUATION	$328,099
														Subtotal = $328,099

Issue Date FY: 2022 ( Subtotal = $328,099 )
2022	2022	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	4	5/23/2022	NON-COMPETING CONTINUATION	$328,099
														Subtotal = $328,099

Issue Date FY: 2021 ( Subtotal = $437,644 )
2021	2021	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	3	5/12/2021	NON-COMPETING CONTINUATION	$437,644
														Subtotal = $437,644

Issue Date FY: 2020 ( Subtotal = $462,990 )
2020	2020	LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER	1124 WEST CARSON ST.	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	5/28/2020	NON-COMPETING CONTINUATION	$462,990
														Subtotal = $462,990

Issue Date FY: 2019 ( Subtotal = $300,838 )
2019	2019	LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE AT HARBOR-UCLA MEDICAL CENTER	1124 W CARSON ST BLDG N-14	TORRANCE	CA	90502	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	5/31/2019	NEW	$300,838
														Subtotal = $300,838

Grand Total All Awards = $1,857,670

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

Award Number: R01AI146078

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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