Therapeutic Development of Antimicrobial Biomimetics

DESCRIPTION (provided by applicant): The incidence of healthcare-acquired infections has increased significantly in recent years and has become an important cause of morbidity and mortality in hospitals in the US and worldwide. The continuing emergence of drug resistance in clinically-important pathogens has now become a global problem and public health threat. In a 2003 Institute of Medicine report, antimicrobial resistance was described as a paramount microbial threat in the 21st Century. It has been estimated that infections caused by drug-resistant organisms double the duration of hospital stays by patients and economic costs for added medical care have been reported to total up to several billion dollars per year in the US. These alarming increases in the emergence of drug-resistant strains and the associated clinical and economic consequences signal the dire need for development of new antimicrobial agents with activity against these organisms. These agents should be novel and attack new targets to evade resistance issues which plague the success of new but structurally-related antibiotics. Furthermore, these agents should exert their antimicrobial activity via mechanisms that bacteria do not effectively resist. The goals of the Phase 2 research plan are to evaluate the suitability of PMX lead candidates in a drug development program leading to human clinical trials for an anti-infective indication. There is substantial information on preclinical in vivo efficacy of the PMX compounds and particular attention will be directed at in vitro screens, acute and repeat dose toxicity studies, safety pharmacology studies and manufacturing to rapidly determine if an IND can be opened to examine safety and tolerability in human subjects. In addition, medicinal chemistry will continue using the base structures of two preferred lead candidates to identify back-up compounds to substitute into the discovery program if problems are encountered with the lead candidates. The projected use for the developed product is as an iv injectable antibiotic to treat hospital-acquired infections.