title: Combined Bioinformatic and Rational Design Approach To Develop Antimicrobial Peptides against Mycobacterium tuberculosis.
abstract: Drug-resistant pathogens are a growing problem, and novel strategies are needed to combat this threat. Among the most significant of these resistant pathogens is Mycobacterium tuberculosis, which is an unusually difficult microbial target due to its complex membrane. Here, we design peptides for specific activity against M. tuberculosis using a combination of "database filtering" bioinformatics, protein engineering, and de novo design. Several variants of these peptides are structurally characterized to validate the design process. The designed peptides exhibit potent activity (MIC values as low as 4 μM) against M. tuberculosis and also exhibit broad activity against a host of other clinically relevant pathogenic bacteria such as Gram-positive bacteria (Streptococcus) and Gram-negative bacteria (Escherichia coli). They also display excellent selectivity, with low cytotoxicity against cultured macrophages and lung epithelial cells. These first-generation antimicrobial peptides serve as a platform for the design of antibiotics and for investigating structure-activity relationships in the context of the M. tuberculosis membrane. The antimicrobial peptide design strategy is expected to be generalizable for any pathogen for which an activity database can be created.
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, RPI, Troy, New York, USA.
authors.forename: C Seth
authors.initials: CS
authors.lastname: Pearson
authors.affiliation: Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Kloos
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, RPI, Troy, New York, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Murray
authors.affiliation: Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
authors.forename: Ebot
authors.initials: E
authors.lastname: Tabe
authors.affiliation: Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, New York, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Gupta
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, RPI, Troy, New York, USA.
authors.forename: Jun Ha
authors.initials: JH
authors.lastname: Kwak
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, RPI, Troy, New York, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Karande
authors.affiliation: Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, New York, USA Department of Biomedical Sciences, University at Albany, SUNY, Albany, New York, USA kathleen.mcdonough@health.ny.gov belfog@rpi.edu.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: McDonough
authors.affiliation: Howard P. Isermann Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, RPI, Troy, New York, USA kathleen.mcdonough@health.ny.gov belfog@rpi.edu.
authors.forename: Georges
authors.initials: G
authors.lastname: Belfort
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides