Methicillin resistant Staphylococcus aureus (MRSA) has become a serious source of life-threatening hospital infections and increasingly community acquired infections. As our current treatments for MRSA infections are losing efficacy, there is an urgent need for new antibiotics to cope with this problem. A recently discovered metabolite, bacillithiol (BSH), has been shown to be present in S. aureus and Bacillus spp., but is absent in human or other higher organisms.
The specific aims of the research are to identify and characterize enzymes involved in BSH metabolism, such as bacillithiol disulfide reductase, and to elucidate S. aureus BSH dependent xenobiotic detoxification pathways. The results of these studies will elaborate the functions of BSH and will establish whether BSH metabolism is a suitable target for staphylococcal drug development. As thiols are known to be involved in the development of drug resistance, this research may provide insight into intrinsic drug resistance in S. aureus.

Public Health Relevance

Staphylococcus aureus is a major human pathogen capable of causing a range of diseases from superficial skin infections to deadly septicemia and toxic shock syndrome. The increase in prevalence of methicillin resistant S. aureus (MRSA) strains and the advent of vancomycin resistant MRSA strains makes it imperative that new drug targets be identified and characterized. Drug detoxification and subsequent resistance pose serious problems to the further treatment of bacterial infections. Thiols have been shown to play a key role in detoxification and thus mechanisms of drug resistance and detoxification in S. aureus be carefully scrutinized in order to find ways to overcome these mechanisms. In this proposal, we identify and characterize potential new drug targets and explore the way S. aureus becomes resistant to existing drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Continuance Award (SC3)
Project #
5SC3GM100855-02
Application #
8469058
Study Section
Special Emphasis Panel (ZGM1-MBRS-9 (SC))
Program Officer
Okita, Richard T
Project Start
2012-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$100,167
Indirect Cost
$27,792
Name
California State University Fresno
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
793751087
City
Fresno
State
CA
Country
United States
Zip Code
93726
Roberts, Alexandra A; Sharma, Sunil V; Strankman, Andrew W et al. (2013) Mechanistic studies of FosB: a divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus. Biochem J 451:69-79
Rajkarnikar, Arishma; Strankman, Andrew; Duran, Shayla et al. (2013) Analysis of mutants disrupted in bacillithiol metabolism in Staphylococcus aureus. Biochem Biophys Res Commun 436:128-33