Marine Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries Research Institute, Ernakulam North, P.B. No. 1603, Cochin, India.
Marine Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries Research Institute, Ernakulam North, P.B. No. 1603, Cochin, India; Faculty of Marine Sciences, Lakeside Campus, Cochin University of Science and Technology, Cochin, Kerala State, India.
Bioorg Chem. 2021 Mar;108:104533. doi: 10.1016/j.bioorg.2020.104533. Epub 2020 Dec 7.
Heterotrophic Gamma-proteobacterium Shewanella algae MTCC 12715, associated with an intertidal red algae Hypnea valentiae, presented broad-spectra of antibacterial activities against pathogenic bacteria bringing about nosocomial infection. Bioassay-guided fractionation of the bacterial crude extract resulted in two undescribed macrocyclic polyketide analogs, with anti-infective activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis (MIC 3.1-5.0 µg/mL). In order to identify the polyketide biosynthetic machinery termed type-I polyketide synthase (pks-I) encoding biologically active secondary metabolites in this strain, the ketosynthase-coding regions of DNA with ≈700 bp size, were amplified, and the partial sequence was submitted in the GenBank (accession number MH157093). The titled compounds were classified under macrocyclic polyketides bearing dodecahydropyrano-trioxacyclooctadecine-dione and trioxo-octadecahydro-1H-benzo[o]tetraoxacyclopentacosine-carboxylate functionalities. Structure-activity correlation analysis displayed that hydrophobic descriptor of the studied compounds could play a prominent role in its anti-infective property against the opportunistic pathogens. Further, in silico molecular docking studies were performed in the allosteric sites of penicillin-binding protein (PBP2a) coded by mecA genes of MRSA, and the best binding pose for each compound (docking score -8.47 kcal/mol and -9.58 kcal/mol, respectively) could be correlated with their in vitro antibacterial activities. The pks-I assisted biosynthetic pathway of macrocyclic polyketides through step-wise decarboxylative condensation initiated by malonate-acyl carrier protein corroborated their structural attributes. Chemical mining of the studied macroalgae-associated heterotrophic bacterium thus revealed the promising antagonistic properties of macrocyclic polyketides isolated from Shewanella algae MTCC 12715 against multidrug-resistant pathogens.
与潮间带红藻 Hypnea valentiae 相关的异养γ-变形菌 Shewanella algae MTCC 12715 对引起医院感染的致病菌表现出广谱的抗菌活性。对细菌粗提取物进行生物测定指导的分段，得到了两种未描述的大环聚酮类似物，对耐甲氧西林金黄色葡萄球菌和耐万古霉素粪肠球菌具有抗感染活性（MIC3.1-5.0μg/mL）。为了鉴定该菌株中具有生物活性的次生代谢产物的 I 型聚酮合酶（pks-I）编码的聚酮生物合成机制，扩增了大小约为 700bp 的酮合酶编码区 DNA，部分序列已在 GenBank 中提交（登录号 MH157093）。标题化合物被归类为具有十二氢吡喃-三氧杂环十八烷-二酮和三氧杂十八氢-1H-苯并[o]四氧杂环二十烷羧酸酯官能团的大环聚酮。构效关系分析表明，研究化合物的疏水性描述符可能在其对机会性病原体的抗感染特性中发挥重要作用。此外，还对耐甲氧西林金黄色葡萄球菌 mecA 基因编码的青霉素结合蛋白（PBP2a）的变构部位进行了计算机分子对接研究，每个化合物的最佳结合构象（对接评分分别为-8.47kcal/mol 和-9.58kcal/mol）与其体外抗菌活性相关。通过丙二酸盐-酰基载体蛋白引发的逐步脱羧缩合，pks-I 辅助的大环聚酮生物合成途径证实了它们的结构特征。对研究的海藻相关异养细菌的化学挖掘揭示了从 Shewanella algae MTCC 12715 中分离出的大环聚酮对多药耐药病原体的潜在拮抗特性。
