Department of Biological Sciences, Bowling Green State University, Bowling Green, Ohio, USA.
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Appl Environ Microbiol. 2019 Nov 14;85(23). doi: 10.1128/AEM.01438-19. Print 2019 Dec 1.
Since the discovery of penicillin, microbes have been a source of antibiotics that inhibit the growth of pathogens. However, with the evolution of multidrug-resistant (MDR) strains, it remains unclear if there is an abundant or limited supply of natural products to be discovered that are effective against MDR isolates. To identify strains that are antagonistic to pathogens, we examined a set of 471 globally derived environmental strains (env-Ps) for activity against a panel of 65 pathogens including spp., spp., , and spp. isolated from the lungs of cystic fibrosis (CF) patients. From more than 30,000 competitive interactions, 1,530 individual inhibitory events were observed. While strains from water habitats were not proportionate in antagonistic activity, MDR CF-derived pathogens (CF-Ps) were less susceptible to inhibition by env-Ps, suggesting that fewer natural products are effective against MDR strains. These results advocate for a directed strategy to identify unique drugs. To facilitate discovery of antibiotics against the most resistant pathogens, we developed a workflow in which phylogenetic and antagonistic data were merged to identify strains that inhibit MDR CF-Ps and subjected those env-Ps to transposon mutagenesis. Six different biosynthetic gene clusters (BGCs) were identified from four strains whose products inhibited pathogens including carbapenem-resistant BGCs were rare in databases, suggesting the production of novel antibiotics. This strategy can be utilized to facilitate the discovery of needed antibiotics that are potentially active against the most drug-resistant pathogens. Carbapenem-resistant is difficult to treat and has been deemed by the World Health Organization as a priority one pathogen for which antibiotics are most urgently needed. Although metagenomics and bioinformatic studies suggest that natural bacteria remain a source of novel compounds, the identification of genes and their products specific to activity against MDR pathogens remains problematic. Here, we examine water-derived pseudomonads and identify gene clusters whose compounds inhibit CF-derived MDR pathogens, including carbapenem-resistant .
自从青霉素被发现以来，微生物一直是抗生素的来源，可以抑制病原体的生长。然而，随着多药耐药（MDR）菌株的进化，目前尚不清楚是否有大量或有限的天然产物供应可以被发现，这些天然产物对 MDR 分离株有效。为了鉴定对病原体具有拮抗作用的菌株，我们检查了一组来自全球环境的 471 株（env-Ps），以评估它们对 65 种病原体的活性，包括从囊性纤维化（CF）患者肺部分离出的 spp.、 spp.、 和 spp.。在超过 30000 次竞争相互作用中，观察到了 1530 个单独的抑制事件。虽然来自水栖息地的菌株在拮抗活性方面不成比例，但 MDR CF 衍生的病原体（CF-Ps）对 env-Ps 的抑制作用较低，这表明针对 MDR 菌株的天然产物较少。这些结果主张采取有针对性的策略来识别独特的药物。为了发现针对最耐药病原体的抗生素，我们开发了一种工作流程，其中将系统发育和拮抗数据合并，以鉴定抑制 MDR CF-Ps 的菌株，并对这些 env-Ps 进行转座子诱变。从四个抑制病原体的菌株中鉴定出六个不同的生物合成基因簇（BGCs），包括碳青霉烯类耐药 BGCs 在数据库中很少见，表明产生了新型抗生素。这种策略可用于促进发现针对最耐药病原体具有潜在活性的所需抗生素。碳青霉烯类耐药 难以治疗，被世界卫生组织视为急需抗生素的优先病原体之一。尽管宏基因组学和生物信息学研究表明，天然细菌仍然是新型化合物的来源，但鉴定针对 MDR 病原体具有活性的基因及其产物仍然存在问题。在这里，我们研究了源自水的假单胞菌，并鉴定了其化合物抑制 CF 衍生的 MDR 病原体的基因簇，包括碳青霉烯类耐药 。
