Novel D-LAK peptides combinations against mycobacteria : bioefficacy and mechanistic studies

Emergence of multidrug-resistant tuberculosis (MDR-TB) renders the two most powerful and commonly used TB antibiotics, rifampicin and isoniazid, ineffective. There is an urgent need for the development of safe and effective strategies against drug-resistant TB. Based on previous studies, two novel antimicrobial peptides, namely D-LAK120-A and D-LAK120-HP13, both consist entirely of D-amino acid residues, have demonstrated inhibitory effect on MDR Mycobacterium tuberculosis (Mtb) strains when cultured in macrophages and potentiated the antimycobacterial activity of isoniazid in vitro. Here, the antimycobacterial activity of D-LAK peptides in combination with anti-TB drugs against MDR-TB clinical isolates was investigated. Furthermore, the mechanisms of action of the proline-containing and proline-free D-LAK peptides, anti-TB drugs alone or in combinations were studied using two mycobacterial models Mycobacterium smegmatis and the severely attenuated Mtb Bleupan. Finally, the applicability of these two microorganisms for mycobacterial studies was discussed. In vitro and ex vivo antimycobacterial assays revealed the synergy between D-LAK peptides and rifampicin or isoniazid against MDR Mtb strain. These findings ... (continues)