In vitro activity and mode of action of diastereomeric antimicrobial peptides against bacterial clinical isolates

• Published in: Journal of antimicrobial chemotherapy Vol. 53; no. 2; pp. 230 - 239
• Main Authors: Pag, U., Oedenkoven, M., Papo, N., Oren, Z., Shai, Y., Sahl, H.-G.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2004; Oxford Publishing Limited (England)
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacteria - drug effects; Bacterial Infections - microbiology; Biological and medical sciences; Culture Media; Cytoplasm - physiology; Drug Synergism; Fluorometry; Fungi - drug effects; Glutamic Acid - metabolism; Humans; Intracellular Membranes - physiology; intracellular targets; Kinetics; Medical sciences; membrane permeabilization; Membrane Potentials - physiology; Microbial Sensitivity Tests; Peptides; Pharmacology. Drug treatments; Stereoisomerism; synergic activities; Infection; Peptides; Bacteriosis; Bacteria; In vitro; Clinical isolate; Biological activity; Antimicrobial agent
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkh083

Objectives: Increasing resistance of pathogenic bacteria to antibiotics is a severe problem in health care and has intensified the search for novel drugs. Cationic antibacterial peptides are the most abundant antibiotics in nature and have been frequently proposed as new anti-infective agents. Here, a group of diastereomeric (containing d- and l-amino acids) peptides is studied regarding their potency against multiply resistant clinical isolates and their modes of action against Gram-positive cocci. Methods: MIC determinations and chequerboard titrations followed established procedures. Mode of action studies included killing kinetics and a series of experiments designed to characterize the impact of the diastereomeric peptides on bacterial membranes. Results: The tested diastereomers displayed high antimicrobial and broad spectrum activity with amphipathic-2D being the most active peptide. Synergic activities were observed with individual strains. Mode of action studies clearly demonstrated that the cytoplasmic membrane is a primary target for the peptides and that membrane disruption constitutes a significant bactericidal activity for the major fraction of a bacterial population. However, depending on the indicator strain, the results also suggest that additional molecular events contribute to the overall activity.