The development of a novel antifungal for drug resistance

ABSTRACT Invasive fungal infections are an underappreciated global health crisis that results in a staggering 2.5 million deaths annually, far greater than that from tuberculosis or malaria. Both the World Health Organization (WHO) and the Centers for Disease Control (CDC) have voiced alarms about the increasing prevalence and virulence of drug-resistant fungal pathogens. These pathogens compared to nonresistant pathogens are associated with increased mortality rates, longer hospitalizations, and increased costs. Invasive fungal infections result in at least $7.2 billion in direct healthcare costs in the United States. There is a large and expanding population of patients that are at high risk of invasive fungal infections, including those that are immunocompromised, critically ill, and those with certain chronic diseases, such as diabetes and asthma. The infections that these at-risk patients develop, often while receiving much- needed treatments, like chemotherapy or organ transplants, are associated with significant mortality. Unfortunately, the three widely prescribed classes of antifungals (AF) – azoles, echinocandins, and polyenes – do little to combat this public health crisis. Thus, there is an urgent need for a novel antifungal that works on a distinct mechanism of action and can combat a broad spectrum of drug-resistant fungi. Our current lead compound, LP10581, addresses many of the current shortcomings in treatment options. For example LP10581 is a novel small-molecular-weight compound (MW=426) that was derived from a compound found in LifePharms’ proprietary natural product collection. It has no toxicity to human or mice cells, has broad in vitro and in vivo activity against drug-resistant fungi, is synergic with most current antifungal drugs, and can be administered orally or intravenously with excellent in vivo activity. .Also, LP10581”s mechanism of action is novel and is consistent with the selective inhibition of fungal heat shock 90 (Hsp90). These unique features of LP10581 make it an excellent starting point from which to synthesize and test a series of analogs in order to find a new lead compound with high activity both in vitro and in vivo. The goal will be to identify compounds with ten times improved antifungal activity and >5 mg/Kg oral activity in mice models. Initially, Dr. Bruce Blough at Research Triangle Institute, will synthesize 50 analogs of LP10581 in batches of three to four and these compounds will be characterized for safely and antifungal activity at LifePharms. These results will provide the necessary feedback for ongoing synthetic efforts. The in vivo efficacy of the two most promising analogs will be conducted by Dr. Mahmoud Ghannoum at Case Western University Mycology Laboratory. The analog of LP10581 with the most potent in vivo activity will be selected for separation of its four isomers. If the antifungal activity resides in one isomer, it could result in a compound with four-fold the potency of the parent analog.