Two Novel Point Mutations in Clinical Staphylococcus aureus Reduce Linezolid Susceptibility and Switch on the Stringent Response to Promote Persistent Infection

• DOI: 10.1371/journal.ppat.1000944
• Publication Date: 2010-06-10T20:31:13Z
• Authors: Wei Gao; Kyra Chua; John K. Davies; Hayley J. Newton; Torsten Seemann; Paul F. Harrison; Natasha E. Holmes; Hyun-Woo Rhee; Jong-In Hong; Elizabeth L. Hart...; Timothy P. Stinear; Benjamin P. Howden
• Keywords: Linezolid; 23S ribosomal RNA

Staphylococcus aureus frequently invades the human bloodstream, leading to life threatening bacteremia and often secondary foci of infection. Failure antibiotic therapy eradicate infection is described; in some cases associated with altered S. antimicrobial resistance or small colony variant (SCV) phenotype. Newer antimicrobials, such as linezolid, remain last available for patients multi-resistant infections. Using comparative functional genomics we investigated molecular determinants SCV formation sequential isolates from a patient who had persistent recurrent infection, after failed multiple including linezolid. Two point mutations key staphylococcal genes dramatically affected clinical behaviour bacterium, altering virulence resistance. Most strikingly, single nucleotide substitution relA (SACOL1689) reduced RelA hydrolase activity caused accumulation intracellular signalling molecule guanosine 3′, 5′-bis(diphosphate) (ppGpp) permanent activation stringent response, which has not previously been reported aureus. isolate defined mutant an identical mutation, demonstrate first time impact active response aureus, was growth, attenuated Galleria mellonella model. In addition, mutation rlmN (SACOL1230), encoding ribosomal methyltransferase that methylates 23S rRNA at position A2503, reduction linezolid susceptibility. These results reinforce exquisite adaptability show how subtle changes cause major alterations bacterial behaviour, well highlighting potential weaknesses current treatment regimens.