Utilization of microbial iron assimilation processes for the development of new antibiotics and inspiration for the design of new anticancer agents

Abstract

Pathogenic microbes rapidly develop resistance to antibiotics. To keep ahead in the "microbial war", extensive interdisciplinary research is needed. A primary cause of drug resistance is the overuse of antibiotics that can result in alteration of microbial permeability, alteration of drug target binding sites, induction of enzymes that destroy antibiotics (ie., beta-lactamase) and even induction of efflux mechanisms. A combination of chemical syntheses, microbiological and biochemical studies demonstrate that the known critical dependence of iron assimilation by microbes for growth and virulence can be exploited for the development of new approaches to antibiotic therapy. Iron recognition and active transport relies on the biosyntheses and use of microbe-selective iron-chelating compounds called siderophores. Our studies, and those of others, demonstrate that siderophores and analogs can be used for iron transport-mediated drug delivery ("Trojan Horse" antibiotics) and induction of iron limitation/starvation (Development of new agents to block iron assimilation). Recent extensions of the use of siderophores for the development of novel potent and selective anticancer agents are also described.

Fig. 1

Synthetic siderophore-drug conjugates, growth curves and outer membrane protein (OMP) profiles of wild-type E. coli X580 and selected “non pathogenic” mutants “resistant to” 1 (1R) and 2 (2R) or the combination of 1 and 2 (1&2R, “double mutant”) because of missing outer membrane siderophore receptors

Fig. 2

Hypothetical reduction triggered drug release in salmycins

Fig. 3

Generalized structure of potential siderophore antibiotics of the future

Fig. 4

Mycobacterial iron uptake and structures of mycobactins and exochelin

Fig. 5

Retrosynthetic plan for mycobactins and analogs

Fig. 6

Improved syntheses of YPX-I-145 for large scale production

Fig. 7

Analogs of YPX-1-145 and other mycobactin analogs with lysine replacements

Fig. 8

Synthetic truncated mycobactins do not have anti-TB activity

Fig. 9

Additional natural mycobactin analogs and their biological activity

Fig. 10

Synthetic amamistatin, its diastereomer, non-iron binding analog and natural mycobatin M