Non-natural antimicrobial peptides are ideal as next generation antibiotics because of their ability to circumvent the problems of drug resistance and in vivo instability. We report novel all-α- and α,γ-mixed Tat peptide analogues as potential antibacterial and anti-TB agents. These peptides have broad spectrum antibacterial activities against Gram-positive (MICs 0.61 ± 0.03 to 1.35 ± 0.21 μM with the peptide γTatM4) and Gram-negative (MICs 0.71 ± 0.005 to 1.26 ± 0.02 μM with γTatM4) bacteria and are also effective against active and dormant forms of Mycobacterium tuberculosis, including strains that are resistant to rifampicin and isoniazid. The introduction of the non-natural amino acids of the study in the Tat peptide analogues results in increased resistance to degradation by proteolysis, significantly increasing their half-life. The peptides appear to inhibit bacteria by a membrane disruption mechanism, and have only a low cytotoxic effect on mammalian cells.

非天然抗菌肽是理想的下一代抗生素，因为它们具有规避耐药性和体内不稳定性问题的能力。我们报告新型的全α-和α，γ混合Tat肽类似物作为潜在的抗菌和抗结核病药物。这些肽具有对革兰氏阳性细菌（MICS为0.61±0.03至1.35±0.21μM，使用肽γTatM4的细菌）和革兰氏阴性细菌（MICs为0.71±0.005至1.26±0.02μM，对于γTatM4）具有广谱的抗菌活性，并且还对活性细菌有效和休眠形式的结核分枝杆菌，包括对利福平和异烟肼具有抗性的菌株。Tat肽类似物中引入了该研究的非天然氨基酸，从而提高了对蛋白水解降解的抵抗力，从而显着延长了其半衰期。这些肽似乎通过膜破坏机制抑制细菌，并且仅对哺乳动物细胞具有低细胞毒性作用。