Lantibiotics represent a large untapped pipeline of attractive scaffolds for the development of novel antibiotics. Saturation mutagenesis was employed to substitute every amino acid of a lantibiotic called mutacin 1140 (MU1140), creating an unbiased expression library of 418 variants that was used to study the permissiveness to mutagenesis and the “drugability” of several compounds. Contrasting previous reports, the results from this study supported that not all residues involved in lanthionine bridge formation were critical for maintaining optimal activity. While substitutions in lanthionine bridges in Ring A, C, and D invariably lead to inactive variants, permissive substitutions in Abu8 and Ala11 (Ring B) were observed, albeit infrequently. Further, the data generated suggested that the unsaturated bond from Dha5 (Ser5) may not be critically involved in Lipid‐II binding but still important for conferring optimal activity. This study identified additional permissive mutations of Ser5, including Ser5His, Ser5Met, Ser5Gln, and Ser5Leu. In contrast, no permissive substitutions were identified for Dhb14, which suggested that this residue may be critical for optimal activity. Novel blueprints are proposed for directing further development of MU1140 variants and other lantibiotics, which may enable the rational design, development, manufacture, and formulation of an entirely new class of anti‐infectives.

中文翻译：

---

合理设计治疗性诱变蛋白1140变体的蓝图

羊毛硫抗生素代表了许多尚未开发的吸引人的支架，用于开发新型抗生素。饱和诱变被用来替代羊毛硫抗生素（mutacin 1140（MU1140））的每个氨基酸，从而创建了一个包含418个变体的无偏表达库，用于研究诱变的允许性和几种化合物的“可药用性”。与以前的报告相反，这项研究的结果支持并非所有参与羊毛硫氨酸桥形成的残基对于维持最佳活性至关重要。虽然在环A，C和D中的羊毛硫氨酸桥中的取代总是会导致无活性的变异，但在Abu8和Ala11（环B）中却观察到了允许的取代，尽管这种情况很少发生。进一步，产生的数据表明，来自Dha5（Ser5）的不饱和键可能不参与Lipid-II的结合，但对于赋予最佳活性仍然很重要。这项研究确定了Ser5的其他允许突变，包括Ser5His，Ser5Met，Ser5Gln和Ser5Leu。相反，没有发现Dhb14的允许取代，这表明该残基可能对最佳活性至关重要。提出了新的蓝图，以指导MU1140变体和其他羊毛硫抗生素的进一步开发，这可能使合理设计，开发，制造和配制全新的抗感染药物成为可能。相反，没有发现Dhb14的允许取代，这表明该残基可能对最佳活性至关重要。提出了新的蓝图，以指导MU1140变体和其他羊毛硫抗生素的进一步开发，这可能使合理设计，开发，制造和配制全新的抗感染药物成为可能。相反，没有发现Dhb14的允许取代，这表明该残基可能对最佳活性至关重要。提出了新的蓝图，以指导MU1140变体和其他羊毛硫抗生素的进一步开发，这可能使合理设计，开发，制造和配制全新的抗感染药物成为可能。