Utilization of microbial iron assimilation processes for the development of new antibiotics and inspiration for the design of new anticancer agents.
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.
Miller
Marvin J
MJ
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA. mmiller1@nd.edu
Zhu
Helen
H
Xu
Yanping
Y
Wu
Chunrui
C
Walz
Andrew J
AJ
Vergne
Anne
A
Roosenberg
John M
JM
Moraski
Garrett
G
Minnick
Albert A
AA
McKee-Dolence
Julia
J
Hu
Jingdan
J
Fennell
Kelley
K
Kurt Dolence
E
E
Dong
Li
L
Franzblau
Scott
S
Malouin
Francois
F
Möllmann
Ute
U
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D001419:Bacteria / Q000235:genetics / Q000378:metabolism*; D016503:Drug Delivery Systems; D015195:Drug Design; D004352:Drug Resistance, Microbial; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism; D017262:Siderophores / Q000737:chemistry / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D010080:Oxazoles; D017262:Siderophores; C018608:mycobactins; D007501:Iron