title: Cationic amphipathic D-enantiomeric antimicrobial peptides with in vitro and ex vivo activity against drug-resistant Mycobacterium tuberculosis.
abstract: Tuberculosis (TB) is the leading cause of bacterial death worldwide. Due to the emergence of multi-drug resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), and the persistence of latent infections, a safe and effective TB therapy is highly sought after. Antimicrobial peptides (AMPs) have therapeutic potential against infectious diseases and have the ability to target microbial pathogens within eukaryotic cells. In the present study, we investigated the activity of a family of six AMPs containing all-D amino acids (D-LAK peptides) against MDR and XDR clinical strains of Mycobacterium tuberculosis (Mtb) both in vitro and, using THP-1 cells as a macrophage model, cultured ex vivo. All the D-LAK peptides successfully inhibited the growth of Mtb in vitro and were similarly effective against MDR and XDR strains. D-LAK peptides effectively broke down the heavy clumping of mycobacteria in broth culture, consistent with a 'detergent-like effect' that could reduce the hydrophobic interactions between the highly lipidic cell walls of the mycobacteria, preventing bacteria cell aggregation. Furthermore, though not able to eradicate the intracellular mycobacteria, D-LAK peptides substantially inhibited the intracellular growth of drug-resistant Mtb clinical isolates at concentrations that were well tolerated by THP-1 cells. Finally, combining D-LAK peptide with isoniazid could enhance the anti-TB efficacy. D-LAK peptide, particularly D-LAK120-A, was effective as an adjunct agent at non-toxic concentration to potentiate the efficacy of isoniazid against drug-resistant Mtb in vitro, possibly by facilitating the access of isoniazid into the mycobacteria by increasing the surface permeability of the pathogen.
authors.affiliation: Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lan
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital, Pokfulam Road, Hong Kong Special Administrative Region.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lam
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Special Administrative Region.
authors.forename: Gilman K H
authors.initials: GK
authors.lastname: Siu
authors.affiliation: Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, University Pathology Building, Queen Mary Hospital, Pokfulam Road, Hong Kong Special Administrative Region.
authors.forename: Wing Cheong
authors.initials: WC
authors.lastname: Yam
authors.affiliation: Institute of Pharmaceutical Science, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: A James
authors.initials: AJ
authors.lastname: Mason
authors.affiliation: Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong Special Administrative Region. Electronic address: jkwlam@hku.hk.
authors.forename: Jenny K W
authors.initials: JK
authors.lastname: Lam
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D004359:Drug Therapy, Combination; D054908:Extensively Drug-Resistant Tuberculosis / Q000382:microbiology; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008264:Macrophages / Q000382:microbiology; D008826:Microbial Sensitivity Tests / Q000379:methods; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology
chemical_list: D023181:Antimicrobial Cationic Peptides; D000995:Antitubercular Agents; D007538:Isoniazid
keywords: Antimicrobial peptides; Clinical isolates; Isoniazid; Multi-drug resistant; THP-1; Tuberculosis