The msaABCR Operon Regulates the Response to Oxidative Stress in Staphylococcus aureus

Abstract

Staphylococcus aureus has evolved a complex regulatory network that controls a multitude of defense mechanisms against the deleterious effects of oxidative stress stimuli, subsequently leading to the pathogen’s survival and persistence in the hosts. Previously, we characterized the msaABCR operon as a regulator of virulence, antibiotic resistance, and the formation of persister cells in S. aureus. Deletion of the msaABCR operon resulted in the downregulation of several genes involved in resistance against oxidative stress. Notably, those included carotenoid biosynthetic genes and the ohr gene, which is involved in resistance against organic hydroperoxides. These findings led us to hypothesize that the msaABCR operon is involved in resisting oxidative stress generated in the presence of both H2O2 and organic hydroperoxides. Here, we report that a protein product of the msaABCR operon (MsaB) transcriptionally regulates the expression of the crtOPQMN operon and the ohr gene to resist in vitro oxidative stresses. In addition to its direct regulation of the crtOPQMN operon and ohr gene, we also show that MsaB is the transcriptional repressor of sarZ (repressor of ohr). Taken together, these results suggest that the msaABCR operon regulates an oxidative stress defense mechanism, which is required to facilitate persistent and recurrent staphylococcal infections. Moving forward, we plan to investigate the role of msaABCR in the persistence of S. aureus under in vivo conditions. IMPORTANCE This study shows the involvement of the msaABCR operon in resisting oxidative stress by Staphylococcus aureus generated under in vitro and ex vivo conditions. We show that MsaB regulates the expression and production of a carotenoid pigment, staphyloxanthin, which is a potent antioxidant in S. aureus. We also demonstrate that MsaB regulates the ohr gene, which is involved in defending against oxidative stress generated by organic hydroperoxides. This study highlights the importance of msaABCR in the survival of S. aureus in the presence of various environmental stimuli that mainly exert oxidative stress. The findings from this study indicate the possibility that msaABCR is involved in the persistence of staphylococcal infections and therefore could be a potential antimicrobial target to overcome recalcitrant staphylococcal infections.

The Role of Macrophages in Staphylococcus aureus Infection

“…Susceptibility to H 2 O 2 was reversed by iron sequestration or perR repressor gene deletion ( 238 ). Another study showed that the msaABCR operon of S. aureus regulates expression of genes involved in oxidative stress ( 239 ). Staphyloxanthin, a carotenoid pigment, is a strong antioxidant which is regulated by cold shock protein (CspA), alongside the organic hydroperoxide resistance gene which defends specifically against oxidative stress caused by organic hydroperoxides.…”

“…Staphyloxanthin, a carotenoid pigment, is a strong antioxidant which is regulated by cold shock protein (CspA), alongside the organic hydroperoxide resistance gene which defends specifically against oxidative stress caused by organic hydroperoxides. This implies involvement of ROS resistance genes in persistence of S. aureus ( 239 ).…”

The role of the msaABCR operon in implant-associated chronic osteomyelitis in Staphylococcus aureus USA300 LAC

“…The msaABCR operon is a four-gene operon that regulates several virulence factors (proteases as well as factors involved in pigmentation, toxin production, and capsule production), biofilm formation, persister cell formation, oxidative stress response, and antibiotic susceptibility in S. aureus [ 31 – 37 ]. We also showed that msaABCR deletion mutants are not defective in growth [ 33 ].…”

Thiol-based redox switches in the major pathogen Staphylococcus aureus

“…In addition, S. aureus encodes two homologs of the thiol-dependent peroxidase Ohr, which are involved in detoxification of organic hydroperoxides, originating from lipid peroxidation (Dubbs and Mongkolsuk 2007;Mongkolsuk and Helmann 2002). The Ohr paralogs are redoxcontrolled by the thiol-based MarR/OhrR-family repressors MgrA and SarZ as well as by MsaB in S. aureus (Chen et al 2011;Pandey et al 2019). However, many other peroxiredoxins respond to oxidative stress, such as Tpx, Bcp or GpxA1 and GpxA2, which remain to be, characterized in future studies.…”