Workgroup Structural Biology of Biosynthetic Enzymes, Helmholtz Institute for Pharmaceutical Research Saarland , Helmholtz Centre for Infection Research, Saarland University , Campus Geb. E8.1 , Saarbrücken 66123 , Germany.
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Department of Microbial Natural Products , Helmholtz Centre for Infection Research, and Department of Pharmaceutical Biotechnology, Saarland University , Campus E8.1 , Saarbrücken 66123 , Germany.
J Am Chem Soc. 2018 Dec 5;140(48):16641-16649. doi: 10.1021/jacs.8b08895. Epub 2018 Nov 27.
To combat the rise of antimicrobial resistance, the discovery of new antibiotics is paramount. Albicidin and cystobactamid are related natural product antibiotics with potent activity against Gram-positive and, crucially, Gram-negative pathogens. AlbA has been reported to neutralize albicidin by binding it with nanomolar affinity. To understand this potential resistance mechanism, we determined structures of AlbA and its complex with albicidin. The structures revealed AlbA to be comprised of two domains, each unexpectedly resembling the multiantibiotic neutralizing protein TipA. Binding of the long albicidin molecule was shared pseudosymmetrically between the two domains. The structure also revealed an unexpected chemical modification of albicidin, which we demonstrate to be promoted by AlbA, and to reduce albicidin potency; we propose a mechanism for this reaction. Overall, our findings suggest that AlbA arose through internal duplication in an ancient TipA-like gene, leading to a new binding scaffold adapted to the sequestration of long-chain antibiotics.
为了应对抗菌药物耐药性的上升，发现新的抗生素至关重要。阿比西林和胱抑素是具有抗革兰氏阳性菌活性的相关天然产物抗生素，对革兰氏阴性菌也具有重要作用。据报道，AlbA 通过以纳摩尔亲和力结合阿比西林来中和它。为了了解这种潜在的耐药机制，我们确定了 AlbA 及其与阿比西林复合物的结构。结构显示 AlbA 由两个结构域组成，每个结构域都出人意料地类似于多抗生素中和蛋白 TipA。长链阿比西林分子的结合在两个结构域之间以伪对称方式共享。该结构还揭示了阿比西林的一种意外化学修饰，我们证明 AlbA 促进了这种修饰，并降低了阿比西林的效力；我们提出了这种反应的机制。总的来说，我们的发现表明 AlbA 是通过古老的 TipA 样基因内部重复产生的，导致了一个新的结合支架，适应于长链抗生素的隔离。
