title: In vitro antibacterial and antimalarial activity of dehydrophenylalanine-containing undecapeptides alone and in combination with drugs.
abstract: A set of three cationic undecapeptides, analogous to the previously reported peptide VS2 (KWΔFWKΔFVKΔFVK), was created by alanine substitution in order to probe the effect of hydrophobicity on peptide activity. The activities of these peptides were determined against Escherichia coli, Staphylococcus aureus and the malaria parasite Plasmodium falciparum. VA1, the closest analogue of VS2, showed five-fold augmented activity [minimum inhibitory concentration (MIC)=10 μM] against the Gram-positive bacterium S. aureus. The designed analogues were non-haemolytic and non-cytotoxic at their MICs and clinically relevant concentrations. By alanine substitution, it was also possible to probe the critical role of tryptophan residues in determining peptide potency. Circular dichroism studies of the peptides in a membrane-mimetic system showed a correlation between peptide helicity and antimicrobial activity. The peptides were also tested in combination with sublethal concentrations of antibiotic drugs (rifampicin and kanamycin) and the antimalarial drug chloroquine. In combination with these drugs, the effect of the peptides was synergistic or additive. These results provide insight into basic design principles for generating new clinically relevant lead peptides. It also provides an alternative strategy where a peptide and a non-peptide drug can be used in combination to battle increasingly drug-resistant microbes.
authors: International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India.
authors: Sarika Pathak
authors: SP
authors: Sharma
authors: Jyotsna
authors: J
authors: Sharma
authors: Shamsher Singh
authors: SS
authors: Kanwar
authors: Virander Singh
authors: VS
authors: Chauhan
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D002942:Circular Dichroism; D004347:Drug Interactions; D004926:Escherichia coli / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000032:analysis; D010963:Plasmodium falciparum / Q000187:drug effects*; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000962:Antimalarials; D023181:Antimicrobial Cationic Peptides; D010649:Phenylalanine; C018632:phenyldehydroalanine