AUTHOR=Yee Rebecca , Feng Jie , Wang Jiou , Chen Jiazhen , Zhang Ying 

TITLE=Identification of Genes Regulating Cell Death in Staphylococcus aureus

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.02199

DOI=10.3389/fmicb.2019.02199

ISSN=1664-302X

ABSTRACT=<p><italic>Staphylococcus aureus</italic> is an opportunistic pathogen that causes acute and chronic infections. Due to <italic>S. aureus</italic>’s highly resistant and persistent nature, it is paramount to identify better drug targets in order to eradicate <italic>S. aureus</italic> infections. Despite the efforts in understanding bacterial cell death, the genes, and pathways of <italic>S. aureus</italic> cell death remain elusive. Here, we performed a genome-wide screen using a transposon mutant library to study the genetic mechanisms involved in <italic>S. aureus</italic> cell death. Using a precisely controlled heat-ramp and acetic acid exposure assays, mutations in 27 core genes (<italic>hsdR1</italic>, <italic>hslO</italic>, <italic>nsaS</italic>, <italic>sspA</italic>, <italic>folD</italic>, <italic>mfd</italic>, <italic>vraF</italic>, <italic>kdpB</italic>, USA300HOU_2684, 0868, 0369, 0420, 1154, 0142, 0930, 2590, 0997, 2559, 0044, 2004, 1209, 0152, 2455, 0154, 2386, 0232, 0350 involved in transporters, transcription, metabolism, peptidases, kinases, transferases, SOS response, nucleic acid, and protein synthesis) caused the bacteria to be more death-resistant. In addition, we identified mutations in 10 core genes (<italic>capA</italic>, <italic>gltT</italic>, <italic>mnhG1</italic>, USA300HOU_1780, 2496, 0200, 2029, 0336, 0329, 2386, involved in transporters, metabolism, transcription, and cell wall synthesis) from heat-ramp and acetic acid that caused the bacteria to be more death-sensitive or with defect in persistence. Interestingly, death-resistant mutants were more virulent than the parental strain USA300 and caused increased mortality in a <italic>Caenorhabditis elegans</italic> infection model. Conversely, death-sensitive mutants were less persistent and formed fewer persister cells upon exposure to different classes of antibiotics. These findings provide new insights into the mechanisms of <italic>S. aureus</italic> cell death and offer new therapeutic targets for developing more effective treatments for infections caused by <italic>S. aureus.</italic></p>