The fungal natural product fusidic acid demonstrates potent activity against <i>Mycoplasma genitalium</i>

Antimicrobial resistance is extremely common in <i>Mycoplasma genitalium</i>, a frequent cause of urethritis in men and cervicitis, vaginitis, and pelvic inflammatory disease in women. Treatment of <i>M. genitalium</i> infections is difficult due to intrinsic and acquired resistance to many antibiotic classes. We undertook a program to identify novel antimicrobials with activity against <i>M. genitalium</i> from fungal natural products. Extracts of <i>Ramularia coccinea</i> contained a molecule with potent activity that was subsequently identified as fusidic acid, a fusidane-type antibiotic that has been in clinical use for decades outside the United States. We found that minimum inhibitory concentrations of fusidic acid ranged from 0.31 to 4 µg/mL among 17 <i>M</i>. <i>genitalium</i> strains including laboratory-passaged and low-passage clinical isolates. Time-kill data indicate that bactericidal killing occurs when <i>M. genitalium</i> is exposed to ≥10 µg/mL for 48 h, comparing favorably to serum concentrations obtained from typical loading dose regimens. Resistance to fusidic acid was associated with mutations in <i>fusA</i> consistent with the known mechanism of action in which fusidic acid inhibits protein synthesis by binding to elongation factor G. Interestingly, no mutants resistant to >10 µg/mL fusidic acid were obtained and a resistant strain containing a F435Y mutation in FusA was impaired for growth <i>in vitro</i>. These data suggest that fusidic acid may be a promising option for the treatment of <i>M. genitalium</i> infections.