DGIMI, Univ Montpellier, INRAE, Montpellier, France.
Nosopharm, Nîmes, France.
mBio. 2022 Feb 22;13(1):e0282621. doi: 10.1128/mbio.02826-21. Epub 2022 Jan 11.
Antibiotic resistance is an increasing threat to human health. A direct link has been established between antimicrobial self-resistance determinants of antibiotic producers, environmental bacteria, and clinical pathogens. Natural odilorhabdins (ODLs) constitute a new family of 10-mer linear cationic peptide antibiotics inhibiting bacterial translation by binding to the 30S subunit of the ribosome. These bioactive secondary metabolites are produced by entomopathogenic bacterial symbiont (), vectored by the soil-dwelling nematodes. ODL-producing Xenorhabdus nematophila symbionts have mechanisms of self-protection. In this study, we cloned the 44.5-kb biosynthetic gene cluster (-BGC) of the symbiont by recombineering and showed that the -acetyltransferase-encoding gene, , is responsible for ODL resistance. acetylation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses showed that OatA targeted the side chain amino group of ODL rare amino acids, leading to a loss of translation inhibition and antibacterial properties. Functional, genomic, and phylogenetic analyses of revealed an exclusive -link to the odilorhabdin BGC, found only in and a specific phylogenetic clade of . This work highlights the coevolution of antibiotic production and self-resistance as ancient features of this unique tripartite complex of host-vector-symbiont interactions without -BGC dissemination by lateral gene transfer. Odilorhabdins (ODLs) constitute a novel antibiotic family with promising properties for treating problematic multidrug-resistant Gram-negative bacterial infections. ODLs are 10-mer linear cationic peptides inhibiting bacterial translation by binding to the small subunit of the ribosome. These natural peptides are produced by Xenorhabdus nematophila, a bacterial symbiont of entomopathogenic nematodes well known to produce large amounts of specialized secondary metabolites. Like other antimicrobial producers, ODL-producing Xenorhabdus nematophila has mechanisms of self-protection. In this study, we cloned the ODL-biosynthetic gene cluster of the symbiont by recombineering and showed that the -acetyltransferase-encoding gene, , is responsible for ODL resistance. acetylation and LC-MS/MS analyses showed that OatA targeted the side chain amino group of ODL rare amino acids, leading to a loss of translation inhibition and antibacterial properties. Functional, genomic, and phylogenetic analyses of revealed the coevolution of antibiotic production and self-resistance as ancient feature of this particular niche in soil invertebrates without resistance dissemination.
抗生素耐药性对人类健康构成日益严重的威胁。抗生素产生菌、环境细菌和临床病原体的抗菌自我耐药决定因素之间已经建立了直接联系。天然奥多雷巴丁（ODLs）构成了一个新的 10 肽线性阳离子肽抗生素家族，通过与核糖体 30S 亚基结合来抑制细菌翻译。这些生物活性次级代谢产物由昆虫病原细菌共生体（）产生，由土壤居住的线虫载体。ODL 产生的 Xenorhabdus nematophila 共生体具有自我保护机制。在这项研究中，我们通过重组工程克隆了共生体的 44.5kb 生物合成基因簇（-BGC），并表明 -乙酰转移酶编码基因，，负责 ODL 抗性。乙酰化和液相色谱-串联质谱（LC-MS/MS）分析表明，OatA 靶向 ODL 稀有氨基酸的侧链氨基，导致翻译抑制和抗菌特性丧失。对 进行功能、基因组和系统发育分析表明，它与 odilorhabdin BGC 有独特的联系，仅在 Xenorhabdus nematophila 和一个特定的系统发育分支中发现。这项工作强调了抗生素产生和自我抗性的共同进化，这是这种独特的宿主-载体-共生体相互作用三方复合体的古老特征，没有通过水平基因转移传播 BGC。奥多雷巴丁（ODLs）构成了一个新的抗生素家族，具有治疗有问题的多药耐药革兰氏阴性细菌感染的有希望的特性。ODLs 是 10 肽线性阳离子肽，通过与核糖体小亚基结合来抑制细菌翻译。这些天然肽由昆虫病原线虫的共生细菌 Xenorhabdus nematophila 产生，该细菌以产生大量专门的次生代谢物而闻名。像其他抗菌剂生产者一样，产生 ODL 的 Xenorhabdus nematophila 具有自我保护机制。在这项研究中，我们通过重组工程克隆了共生体的 ODL 生物合成基因簇，并表明 -乙酰转移酶编码基因，，负责 ODL 抗性。OatA 乙酰化和 LC-MS/MS 分析表明，OatA 靶向 ODL 稀有氨基酸的侧链氨基，导致翻译抑制和抗菌特性丧失。对 进行功能、基因组和系统发育分析表明，抗生素产生和自我抗性的共同进化是土壤无脊椎动物这一特定生态位的古老特征，没有抗性传播。
