Bacillithiol: a key protective thiol in Staphylococcusaureus

Abstract

Bacillithiol is a low-molecular-weight thiol analogous to glutathione and is found in several Firmicutes, including Staphylococcus aureus. Since its discovery in 2009, bacillithiol has been a topic of interest because it has been found to contribute to resistance during oxidative stress and detoxification of electrophiles, such as the antibiotic fosfomycin, in S. aureus. The rapid increase in resistance of methicillin-resistant Staphylococcus aureus (MRSA) to available therapeutic agents is a great health concern, and many research efforts are focused on identifying new drugs and targets to combat this organism. This review describes the discovery of bacillithiol, studies that have elucidated the physiological roles of this molecule in S. aureus and other Bacilli, and the contribution of bacillithiol to S. aureus fitness during pathogenesis. Additionally, the bacillithiol biosynthesis pathway is evaluated as a novel drug target that can be utilized in combination with existing therapies to treat S. aureus infections.

Keywords:

• bacillithiol
• bacillithiol conjugate amidase
• drug resistance
• fosfomycin
• oxidative stress
• pathogenesis
• Staphylococcus aureus

Acknowledgements

We thank Dr Alan Derman and Eammon Riley for their insightful comments on the review. We also thank Dr James LaClair for ChemDraw3D structures of bacillithiol.

Financial & competing interests disclosure

This research was supported by the National Institutes of Health (R01-AI095125). Kit Pogliano is a founder of Linnaeus Bioscience Incorporated, holds equity interest in the company and receives consulting income. This arrangement has been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Bacillithiol is a recently discovered low-molecular-weight thiol found in the Firmicutes, which include the pathogens Staphylococcus aureus and Bacillus anthracis.

• The low-molecular-weight thiols bacillithiol and mycothiol are related by their Cys-glucosamine core moiety.

• In S. aureus, three unlinked genes encode the bacillithiol biosynthesis enzymes, which are each essential for bacillithiol biosynthesis.

• The BshB enzyme has dual activities: it is a deacetylase utilized in the second step of bacillithiol biosynthesis and a bacillithiol conjugate amidase that can cleave S-conjugates.

• Compared to other low-molecular-weight thiols found in bacteria, bacillithiol has structural differences that make it more reactive with hydrogen peroxide, xenobiotics and drugs, particularly fosfomycin.

• Bacillithiol is the thiol cofactor of the enzyme FosB. Collectively, bacillithiol and FosB-derived fosfomycin resistance is the major detoxification mechanism of multi-drug resistant Staphylococcus aureus to fosfomycin.

• S. aureus mutants deficient in bacillithiol are more susceptible to killing by macrophages, neutrophils and whole blood.

• A possible new strategy for treatment of multidrug resistant Staphylococcus aureus is the combination therapy of a bacillithiol biosynthesis inhibitor with fosfomycin.

Notes