De novo design of selective antibiotic peptides by incorporation of unnatural amino acids.
The evolution of drug-resistant bacteria is one of the most critical problems facing modern medicine and requires the development of new drugs that exhibit their antibacterial activity via novel mechanisms of action. One potential source of new drugs could be the naturally occurring peptides that exhibit antimicrobial activity via membrane disruption. To develop antimicrobial peptides exhibiting increased potency and selectivity against Gram positive, Gram negative, and Mycobacterium bacteria coupled with reduced hemolytic activity, peptides containing unnatural amino acids have been designed, synthesized, and evaluated. These compounds were designed on the basis of the electrostatic surface potential maps derived from the NMR determined SDS and DPC micelle-bound conformations of (Ala8,13,18)magainin-2 amide. Unnatural amino acids were incorporated into the polypeptide backbone to control the structural and physicochemical properties of the peptides to introduce organism selectivity and potency. The methods and results of this investigation are described below.
Hicks
Rickey P
RP
Division of Experimental Therapeutics, Walter Reed Army Institute of Research 503 Robert Grant Avenue, Silver Spring, Maryland 20910, USA. hicksr@ecu.edu
Bhonsle
Jayendra B
JB
Venugopal
Divakaramenon
D
Koser
Brandon W
BW
Magill
Alan J
AJ
D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006461:Hemolysis; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D012867:Skin / Q000293:injuries; D055672:Static Electricity; D014945:Wound Healing / Q000187:drug effects
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D010455:Peptides