title: TXA497 as a topical antibacterial agent: comparative antistaphylococcal, skin deposition, and skin permeation studies with mupirocin.
abstract: TXA497 is representative of a new class of guanidinomethyl biaryl compounds that exhibit potent bactericidal behavior against methicillin-resistant Staphylococcus aureus (MRSA). In this study, we compared the anti-staphylococcal, skin deposition, and skin permeation properties of TXA497 and the topical anti-MRSA antibiotic mupirocin. The results of minimum inhibitory concentration (MIC) assays revealed that TXA497 retains potent activity against MRSA that is highly resistant to mupirocin. Using Franz diffusion cells, compound deposition into human cadaver skin was evaluated, and the results showed the skin deposition of TXA497 to be significantly greater than that of mupirocin. Moreover, unlike mupirocin, TXA497 does not pass through the entire skin layer, suggesting a minimal potential for the systemic absorption of the compound upon topical administration. Additionally, antibacterial concentrations of TXA497 showed no significant toxicity to primary human keratinocytes. Given the rising levels of mupirocin resistance among MRSA populations, our results are significant in that they highlight TXA497 as a potentially useful alternative therapy for treating MRSA skin infections that are resistant to mupirocin.
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08855, USA; Center for Dermal Research, Life Sciences Building, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Mania
authors.initials: M
authors.lastname: Dorrani
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635, USA.
authors.forename: Malvika
authors.initials: M
authors.lastname: Kaul
authors.affiliation: TAXIS Pharmaceuticals, Inc., North Brunswick, NJ 08902, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Parhi
authors.affiliation: Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08855, USA.
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: LaVoie
authors.affiliation: Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635, USA. Electronic address: pilchds@rwjms.rutgers.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pilch
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08855, USA; Center for Dermal Research, Life Sciences Building, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. Electronic address: michniak@dls.rutgers.edu.
authors.forename: Bozena
authors.initials: B
authors.lastname: Michniak-Kohn
mesh_terms: D000279:Administration, Cutaneous; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D006146:Guanidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D016712:Mupirocin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D001713:Biphenyl Compounds; D006146:Guanidines; C000602146:TXA497; D016712:Mupirocin
keywords: MRSA; MSSA; Mupirocin; Skin permeation; TXA497; Topical anti-bacterial