Toward new therapeutics for skin and soft tissue infections: propargyl-linked antifolates are potent inhibitors of MRSA and Streptococcus pyogenes

• Published in: PloS one 2012-02, Vol.7 (2), p.e29434-e29434
• Main Authors: Viswanathan, Kishore, Frey, Kathleen M, Scocchera, Eric W, Martin, Brooke D, Swain Iii, P Whitney, Alverson, Jeremy B, Priestley, Nigel D, Anderson, Amy C, Wright, Dennis L
• Format: Article
• Language: English
• Subjects: Alkynes - therapeutic use; Anti-Bacterial Agents; Antibacterial activity; Antibacterial agents; Antibiotics; Bacteria; Biology; Chemistry; Clinical isolates; Communities; Cross infection; Cryptosporidium hominis; Cytotoxicity; Dihydrofolate reductase; Drug development; Drug resistance; Drug Resistance, Bacterial; Enzymes; Folic Acid Antagonists - therapeutic use; Gram-positive bacteria; Health aspects; Health care; Health care costs; Infections; Inhibitors; Laboratories; Mammalian cells; Medicine; Methicillin; Methicillin-Resistant Staphylococcus aureus - drug effects; Microbial Sensitivity Tests; Minimum inhibitory concentration; Mortality; Nosocomial infections; Pathogens; Pharmaceutical sciences; Public health; Skin; Skin Diseases - drug therapy; Skin Diseases - microbiology; Soft Tissue Infections - drug therapy; Soft Tissue Infections - microbiology; Species Specificity; Staphylococcal infections; Staphylococcus; Staphylococcus aureus; Staphylococcus infections; Strains (organisms); Streptococcus infections; Streptococcus pyogenes; Streptococcus pyogenes - drug effects; Tetrahydrofolate dehydrogenase; Toxicity; Toxoplasma gondii; Vancomycin; Vancomycin - pharmacology; Vitamin B
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0029434

Hospital- and community-acquired, complicated skin and soft tissue infections, often attributed to Staphylococcus aureus and Streptococcus pyogenes, present a significant health burden that is associated with increased health care costs and mortality. As these two species are difficult to discern on diagnosis and are associated with differential profiles of drug resistance, the development of an efficacious antibacterial agent that targets both organisms is a high priority. Herein we describe a structure-based drug development effort that has produced highly potent inhibitors of dihydrofolate reductase from both species. Optimized propargyl-linked antifolates containing a key pyridyl substituent display antibacterial activity against both methicillin-resistant S. aureus and S. pyogenes at MIC values below 0.1 µg/mL and minimal cytotoxicity against mammalian cells. Further evaluation against a panel of clinical isolates shows good efficacy against a range of important phenotypes such as hospital- and community-acquired strains as well as strains resistant to vancomycin.