EFFLUX PUMP OF THE PROTON ANTIPORTER FAMILY CONFERS LOW-LEVEL FLUOROQUINOLONE RESISTANCE IN MYCOBACTERIUM-SMEGMATIS

Due to the resurgence of tuberculosis and the emergence of multidrug-r esistant strains, fluoroquinolones (PQ) are being used in selected tub erculosis patients, but PQ-resistant strains of Mycobacterium tubercul osis have rapidly begun to appear. The mechanisms involved in FQ resis tance need to be elucidated if the effectiveness of this class of anti biotics is to be improved and prolonged. By using the rapid-growing My cobacterium smegmatis as a model genetic system, a gene was selected t hat confers low-level FQ resistance when present on a multicopy plasmi d. This gene, lfrA, encodes a putative membrane efflux pump of the maj or facilitator family, which appears to recognize the hydrophilic FQ, ethidium bromide, acridine, and some quaternary ammonium compounds. it is homologous to qacA from Staphylococcus aureus, tcmA, of Streptomyc es glaucescens, and actII and mmr, both from Streptomyces coelicoler. Increased expression of lfrA augments the appearance of subsequent mut ations to higher-level FQ resistance.