The incidence of aspergillosis, and other invasive mould infections (IMIs), is increasing in hospitals worldwide at an alarming rate. These infections occur primarily in neutropenic patients undergoing cancer chemotherapy and in transplant centers where patients are undergoing immunosuppressive therapy. The treatments employed for these infections consist of the currently available antifungal drugs, often in combination, with failures approaching 50% and high associated mortality. Where successful, treatments are usually long term and usually prolong the hospitalization of the patient. Aspergillus fumigatus, and other Aspergillus species account for about 70% of IMIs, the remainder caused by Scedosporium, Cryptococcus, Fusarium, Rhizopus and other moulds. Current development of antifungal drugs has always targeted Candida infections and has not focused on Aspergillus and other invasive moulds. The ambruticins, polyketides with unusual structures discovered in the 1970s and 1990s from different strains of the myxobacterium Sorangium cellulosum, have high potencies against a number of Aspergillus strains, good oral bioavailability and excellent safety profiles in laboratory animals. In this Phase I proposal, we will make a number of semisynthetic analogs of ambruticin S and ambruticin VS4 and determine their in vitro potencies against a number of Aspergillus species, Cryptococcus, Rhizopus, Scedosporium and Fusarium species. Other in vitro experiments will include the determination of synergy or antagonism of ambruticin with other antifungal agents, and determination of the post-antibiotic effect of these compounds. We will also determine the pharmacokinetic parameters and LD50 of selected compounds. Results obtained during the one year granting period will allow us to make intelligent and systematic choices of molecules for animal efficacy and IND-enabling studies in subsequent Phase II research
