# NIH grant: Fusidic acid for the treatment of drug-resistant Mycoplasma genitalium: in vitro activity, in vivo efficacy, and potential for clinical use (1R21AI199062-01) — retained record

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NIH grant 1R21AI199062-01: Fusidic acid for the treatment of drug-resistant Mycoplasma genitalium: in vitro activity, in vivo efficacy, and potential for clinical use
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Gwendolyn  Wood. Award: $427625.
Start: 2026-07-10T00:00:00.
PROJECT SUMMARY
Mycoplasma genitalium is a sexually transmitted bacterial pathogen that infects both men and women. Recent
surveillance data indicate a prevalence of 17% among individuals attending sexual health clinics, including
27% of men with urethritis and 21%, 12%, and 15% of women with vaginitis, cervicitis, and pelvic inflammatory
disease, respectively. Unfortunately, few treatments are active against this organism. M. genitalium lacks a cell
wall and has only a single membrane, making it intrinsically resistant to antibiotics targeting peptidoglycan
synthesis or the outer membrane. Doxycycline is only 30–40% effective, and azithromycin—once the preferred
therapy—has lost efficacy, with over 60% of U.S. strains now resistant. In high-risk populations, azithromycin
resistance approaches 100%. Resistance to moxifloxacin, the recommended second-line therapy, exceeds
10% and most of these strains are also resistant to macrolides, contributing to an increasing number of
infections that are difficult to treat. The CDC recommends minocycline for dual-resistant infections, but its
efficacy is limited (60–70%), and no highly effective treatments are currently approved in the U.S. Moxifloxacin
is also contraindicated in certain populations (e.g., pregnant women, adolescents <18 years), and the FDA
discourages fluoroquinolone use unless no alternatives exist due to potential serious side effects. There is an
urgent need for additional therapies for M. genitalium infections. We recently found that M. genitalium is
susceptible in vitro to fusidic acid, an antibiotic in clinical use outside the US for decades. Building on our
preliminary data we propose to define the in vitro activity of fusidic acid against M. genitalium in detail.
Susceptibility will be assessed in terms of minimum inhibitory concentrations, time killing kinetics, biofilm
activity, post antibiotic effect, and resistance rates using broth adapted and low passage clinical isolates of M.
genitalium including susceptible and multidrug resistant strains. Mutants with reduced susceptibility to fusidic
acid have been selected in vitro and genome sequencing identified mutations in the fusA gene consistent with
binding to elongation factor G to inhibit protein synthesis, the known mechanism of action. These mutants
remain susceptible to fusidic acid concentrations obtained in serum of loading dosed individuals. Furthermore,
the in vitro doubling time of one mutant was more than twice that of the parent strain indicating a fitness defect.
We will characterize additional resistant isolates obtained spontaneously and through targeted mutations to
define the changes in fusA and other loci that affect the minimum inhibitory concentration and growth rate. In
addition, we will assess whether compensatory mutations can restore normal growth in these mutants. Finally,
we will use a mouse model of vaginal infection to assess in vivo fitness of resistant mutants and efficacy of
fusidic acid against wild type and resistant strains. This study will directly inform the potential of fusidic acid, a
drug with considerable pharmacokinetic and safety data, to treat M. genitalium infections in men and women.
```



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