Investigation of Isobactin Analogues of Teixobactin

Although teixobactin is a promising antibiotic drug candidate against Gram-positive bacteria, it aggregates to form gels that may limit intravenous administration. We previously reported O-acyl isopeptide prodrugs of teixobactin analogues that address the problem of gel formation while retaining antibiotic activity. We termed these compounds isobactins. In the current Letter, we present nine new isobactin analogues that exhibit a reduced propensity to form gels in aqueous conditions while maintaining potent antibiotic activity against MRSA, VRE, and other Gram-positive bacteria. These isobactin analogues contain commercially available amino acid residues at position 10, replacing the synthetically challenging l-allo-enduracididine residue that is present in teixobactin. The isobactins undergo clean conversion to their corresponding teixobactin analogues at physiological pH and exhibit little to no hemolytic activity or cytotoxicity. Because isobactin analogues exhibit enhanced solubility, delayed gel formation, and are more synthetically accessible, it is anticipated that isobactin prodrug analogues may be superior drug candidates to teixobactin.