Antimicrobial Peptides Under Clinical Trials

Abstract

Today microbial drug resistance has become a serious problem not only within inpatient setting but also within outpatient setting. Repeated intake and unnecessary usage of antibiotics as well as the transfer of resistance genes are the most important factors that make the microorganisms resistant to conventional antibiotics. A large number of antimicrobials successfully used for prophylaxis and therapeutic purposes have now become ineffective [1, 2]. Therefore, new molecules are being studied to be used in the treatment of various diseases. Some of these molecules are structural compounds based on a combination of peptides, for example, naturally occurring endogenous peptide antibiotics and their synthetic analogues or molecules designed de novo using QSAR (quantitative structureproperty relationships)-based methods [3]. Trying to exploit numerous advantages of antimicrobial peptides such as high potency and selectivity, broad range of targets, potentially low toxicity and low accumulation in tissues, pharmaceutical industry aims to develop them as commercially available drugs and appropriate clinical trials are being conducted [4]. In this paper we define clinical trials steps and describe current status of several antimicrobial peptides under clinical development as well as briefly depict peptide drug formulation.

Antimicrobial peptides under clinical investigation

“…Like other AMPs, its α‐helical secondary structure is amphipathic with a net positive charge, and it exerts antimicrobial activity via membrane disruption, as well as immunomodulation. The phase II clinical trial was completed by Pacgen Biopharmaceuticals for a mouth rinse treatment for oral candidiasis in HIV patients …”

“…Membrane disruption is known to be its mechanism of action. Two peptides, Novexatin ( 20 ) and Novamycin ( 34 , Table ), are simple peptides composed of arginines with a charge‐to‐length ratio (CTLR) of unity …”

“…The phase I trial is ongoing in Canada for bacterial infections. Fast Track designation from the FDA has been given to this peptide for the treatment of oral mucositis …”

“…Pexiganan was originally developed by Magainin Pharmaceuticals for the treatment of infected diabetic foot ulcers. In 1999, the new drug application (NDA) for its topical administration was eventually rejected by the FDA because there was no advantage compared with a conventional antibiotic drug . In phase III clinical trials, the safety and efficacy of topically applied pexiganan and orally administered ofloxacin (a fluoroquinolone antibiotic) were compared, and the former failed to overcome the noninferiority margin.…”

“…It presents a rapid bactericidal activity against C. difficile by disrupting bacterial cell membranes. In a phase III clinical study conducted by Cubist Pharmaceuticals (later acquired by Merck), surotomycin failed to prove superiority over vancomycin for the oral treatment of C. difficile infection …”