Abstract
Gaining an insight into the mechanism underlying antimicrobial-resistance development in Staphylococcus aureus is crucial for identifying effective antimicrobials. We isolated S. aureus sequence type 72 from a patient in whom the S. aureus infection was highly resistant to various antibiotics and lysostaphin, but no known resistance mechanisms could explain the mechanism of lysostaphin resistance. Genome-sequencing followed by subtractive and functional genomics revealed that serine hydroxymethyltransferase (glyA or shmT gene) plays a key role in lysostaphin resistance. Serine hydroxymethyltransferase (SHMT) is indispensable for the one-carbon metabolism of serine/glycine interconversion and is linked to folate metabolism. Functional studies revealed the involvement of SHMT in lysostaphin resistance, as ΔshmT was susceptible to the lysostaphin, while complementation of the knockout expressing shmT restored resistance against lysostaphin. In addition, the ΔshmT showed reduced virulence under in vitro (mammalian cell lines infection) and in vivo (wax-worm infection) models. The SHMT inhibitor, serine hydroxymethyltransferase inhibitor 1 (SHIN1), protected the 50% of the wax-worm infected with wild type S. aureus. These results suggest SHMT is relevant to the extreme susceptibility to lysostaphin and the host immune system. Thus, the current study established that SHMT plays a key role in lysostaphin resistance development and in determining the virulence potential of multiple drug-resistant S. aureus.
Highlights
Exposure of bacterial pathogens to antibiotic stress, resulting in the clonal selection of antibiotic-resistant bacterial pathogens, poses a threat to human society and healthcare systems [1,2]
We found that K07-204, a human isolate of ST72, displayed resistance against lysostaphin, which was further confirmed by the colony forming unit (CFU) assay and confocal and scanning electron microscopy; based on these analyses, this strain was identified as lysostaphin-resistant isolate of ST72
As growing evidence supports the hypothesis that ST72 isolates are resistant to various antibiotics, it is necessary to test whether lysostaphin can be used for treating antimicrobial resistance (AMR) ST72 infections
Summary
Exposure of bacterial pathogens to antibiotic stress, resulting in the clonal selection of antibiotic-resistant bacterial pathogens, poses a threat to human society and healthcare systems [1,2]. Among the various antimicrobial resistance (AMR) bacterial pathogens, Staphylococcus aureus is one of the leading causes of diseases ranging from skin and soft tissue infections (SSTI) to lethal sepsis, pneumonia, and endocarditis [3,4,5]. Various studies have revealed the presence of multiple sequence types in community and hospital-associated methicillin-resistant S. aureus (MRSA) strains worldwide, including in South Korea [10]. The ever-increasing AMR clones of bacterial pathogens have prompted scientists to develop alternative therapies [12,13,14] against novel potential antimicrobial targets to combat the multiple drug resistant (MDR) infections in community as well as hospital settings [15]
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