Macrocyclic polyketides with siderophore mode of action from marine heterotrophic Shewanella algae : Prospective anti‐infective leads attenuate drug‐resistant pathogens

Abstract

Aims Biotechnological and chemical characterization of previously undescribed homologous siderophore‐type macrocyclic polyketides from heterotrophic Shewanella algae Microbial Type Culture Collection (MTCC) 12715 affiliated with Rhodophycean macroalga Hypnea valentiae of marine origin, with significant anti‐infective potential against drug‐resistant pathogens. Methods and Results The heterotrophic bacterial strain in symbiotic association with intertidal macroalga H. valentiae was isolated to homogeneity in a culture‐dependent method and screened for bioactivities by spot‐over‐lawn assay. The bacterial organic extract was purified and characterized by extensive chromatographic and spectroscopic methods, respectively, and was assessed for antibacterial activities with disc diffusion and microtube dilution methods. The macrocyclic polyketide compounds exhibited wide‐spectrum of anti‐infective potential against clinically significant vancomycin‐resistant Enterococcus faecalis (VREfs), methicillin‐resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and Klebsiella pneumonia with minimum inhibitory concentration of about 1–3 µg ml−1, insomuch as the antibiotics chloramphenicol and ampicillin were active at ≥6·25 µg ml−1. The studied compounds unveiled Fe3+ chelating activity, which designated that their prospective anti‐infective activities against the pathogens could be due to their siderophore mechanism of action. In support of that, the bacterium exhibited siderophore production on bioassay involving the cast upon culture agar plate, and the presence of siderophore biosynthetic gene (≈1000 bp) (MF 981936) further corroborated the inference. In silico molecular modelling with penicillin‐binding protein (PBP2a) coded by mecA genes of MRSA (docking score −11·68 to −12·69 kcal mol−1) verified their in vitro antibacterial activities. Putative biosynthetic pathway of macrocyclic polyketides through stepwise decarboxylative condensation initiated by malonate‐acyl carrier protein further validated their structural and molecular attributes. Conclusions The studied siderophore‐type macrocyclic polyketides from S. algae MTCC 12715 with significant anti‐infective potential could be considered as promising candidates for pharmaceutical and biotechnological applications, especially against emerging multidrug‐resistant pathogens. Significance and Impact of the Study This study exhibited the heterotrophic bacteria in association with intertidal macroalga as propitious biological resources to biosynthesize novel antibacterial agents.

Marine natural products

“…68 As with previous reviews in this series, a number of new bacterial MNPs were claimed during 2021, but the structures presented were not fully consistent with the spectroscopic evidence provided. 7,30,31 The rst total syntheses of 22 marine bacterial compounds was reported in the literature during 2021, caprolactin C 6, 5 akazaoxime 4 and A-76356 45, 16 MA026 67, 25 xiamycins D and E, 69 bacicyclin, 70 (+)-pseudonocardide A and (+)-pseudonocardide C, 71 nocardiotide A, 72 three 2-(p-hydroxybenzyl)prodigiosin-based MNPs, along with isoheptylprodigiosin, and tambjamine MYP1, 73 (+)-spiroindimicin A, 74 nesteretal A, 75 (+)-03219A, 76 enterocin, 77 nahuoic acid A, 78 piscibactin, 79 and aldgamycin N. 80 Over 80 reviews featuring some aspect of marine bacterial chemistry or biology were published during 2021. This is the highest number of reviews ever and no doubt reects the impact that COVID-19 has had on labs around the world.…”

“…Chemical mining of Shewanella algae extracts identified four new macrocyclic polyketides 93–96 . 30,31 Whilst a total of 20 genera of marine-derived bacteria contributed to new chemistry reported in 2021, the genus Streptomyces continues to be the predominant source with 120 metabolites. The new MNPs from this prolific genus included two antibacterial spirotetronate derivatives, lobophorins L 97 and M 98 , 32 two trioxacarcins congeners 99 , 100 , 33 cytotoxic isoquinolinequinones named mansouramycins E–G 101–103 , 34 a rare benzo[ f ]isoindole-dione alkaloid 104 , 35 linear azole-containing peptides spongiicolazolicins A 105 and B 106 , 36 antimycin-type depsipeptides, zhaoshumycins A 107 and B 108 , 37 along with four antimicrobial chlorinated carbazole alkaloids named chlocarbazomycins A–D 109–112 .…”

Discovery of Marine Natural Products as Promising Antibiotics against Pseudomonas aeruginosa

“…Two new siderophore-type hydroxyfuranyl-benzoate spanned 12-membered macrocyclic polyketides 23 and 24 were isolated from Shewanella algae MTCC 12715, and displayed broad antibacterial activities against multiple clinical pathogens including MRSA (inhibition zones of 23 mm and 29 mm, respectively) and P. aeruginosa (inhibition zones of 21 mm and 24 mm, respectively) [ 41 ]. In order to verify their in vitro anti-microbial activities against MRSA, in silicon docking studies for 23 and 24 with penicillin-binding protein 2a (PBP2a), a transpeptidase that catalyzes cell-wall crosslinking to counter the effect of β-lactam antibiotics.…”

“…Docking studies indicated that both compounds could occupy the allosteric site of PBP2a with predicted K i values of 17.51 nM and 3.57 nM, respectively. Besides, compound 24 has a higher drug-likeness score of 0.91 than that of 23 [ 41 ].…”

Exploring Oceans for Curative Compounds: Potential New Antimicrobial and Anti-Virulence Molecules against Pseudomonas aeruginosa

“…The molecules were chemically characterized as 14-(14b,14c-dimethylbutyl)-12-methoxy-18-oxo-11,15-dioxacyclododecan-8-yl 1-((50-hydroxyfuran-10-yl)oxy)benzoate ( 1 ), and 14-(sec-butyl)-12-methoxy-12-methyl-18-oxo-11,15-dioxacyclododecan-8-yl1-((50-hydroxyfuran-10-yl)oxy)benzoate ( 2 ). Compounds 1 and 2 showed antimicrobial activity against P. aeruginosa with an inhibition halo of 21 and 24 mm diameter in DDA and MIC values of 1.5 and 3 µg/mL, respectively [ 135 ].…”