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.