Impaired alanine transport or exposure to D-cycloserine increases the susceptibility of MRSA to β-lactam antibiotics

Abstract

AbstractProlonging the clinical effectiveness of β-lactams, which remain first-line antibiotics for many infections, is an important part of efforts to address antimicrobial resistance. We report here that inactivation of the predicted D-cycloserine (DCS) transporter genecycAre-sensitized MRSA to β-lactam antibiotics. ThecycAmutation also resulted in hyper-susceptibility to DCS, an alanine analogue antibiotic that inhibits alanine racemase and D-alanine ligase required for D-alanine incorporation into cell wall peptidoglycan (PG). Alanine transport was impaired in thecycAmutant and this correlated with increased susceptibility to oxacillin and DCS. ThecycAmutation or exposure to DCS were both associated with the accumulation of muropeptides with tripeptide stems lacking the terminal D-ala-D-ala and reduced PG crosslinking, prompting us to investigate synergism between β-lactams and DCS. DCS re-sensitised MRSA to β-lactamsin vitroand significantly enhanced MRSA eradication by oxacillin in a mouse bacteraemia model. These findings reveal alanine transport as a new therapeutic target to enhance the susceptibility of MRSA to β-lactam antibiotics.