Biosynthetic gene cluster and antimicrobial activity of the elfamycin antibiotic factumycin

Gram negative pathogens are becoming increasingly antibiotic resistant and consequently a serious clinical challenge. We screened a library of Actinomycetes collected across a number of environments in Cuba for the production of metabolites that inhibited the growth of the pathogenic multidrug resistant Gram negative pathogen Acinetobacter baumannii. One of these actinomycetes, WAC5292, produced a compound with selective antibiotic activity vs. Gram negative bacteria. Activity-guided purification of the active metabolite identified the known elfamycin antibiotic factumycin. Draft sequencing of the genome of WAC5292 identified the factumycin biosynthetic cluster containing genes that account for the structure of the antibiotic. Self-resistance is achieved through the action of an ABC transporter, FacT as evidenced by heterologous expression in the factumycin-sensitive organism Streptomyces coelicolor M1154. A screen of factumycin in combination with known antibiotics revealed unexpected synergy with tetracyclines, offering a possible new application of factumycin as a lead in Gram-negative targeted antibiotic combination therapy.