Developing New Methods to Combat Multiple Drug-Resistant Staphylococcus aureus Infection

In 2005 deaths caused by bacterial infections involving Methicillin-resistant Staphylococcus aureus (MRSA) surpassed the mortality rate of A.I.D.S. in the U.S. In addition to being resistant to multiple antibiotics, slow or non-growing MRSA cells are more resistant to all antibiotics, which contributes to infections that may persist for long periods. For these and other reasons, the development of novel treatments and a better understanding of the physiology of S. aureus are of great importance in combating MRSA infections. Recently, an antipsychotic drug called thioridazine was shown to kill growing and non-growing cells of Mycobacterium tuberculosis, though the exact mode of action is unknown. This study aims to identify if thioridazine also kills S. aureus in growing and non-growing states as well as to confirm its exact mode of action. Its activity against S. aureus was tested against both growing and non-growing cultures, and we found that thioridazine rapidly kills actively growing S. aureus at concentrations above 12.5ug/mL. However, like many other agents it is less effective against non-growing cultures even at high concentrations. Interestingly, S. aureus could be enriched to grow at elevated concentrations of thioridazine by serial exposure to low levels of the drug, but the resulting resistance was unstable indicating a phenotypic rather than genotypic mode of resistance. Hence, to obtain genetically-resistant mutants for further study, we exposed cells to a chemical mutagen and selected stable mutants showing elevated levels of resistance to thioridazine.