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Moving away from traditional antibiotic treatment: can macrocyclic lactones from marine macroalga-associated heterotroph be the alternatives?

  • Applied genetics and molecular biotechnology
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Abstract

Intertidal red algae Hypnea valentiae associated Bacillus amyloliquefaciens MTCC 12716 revealed potential inhibitory effects on the growth of drug-resistant pathogens. In the genome of B. amyloliquefaciens MTCC 12716, biosynthetic gene clusters encoding antibacterial metabolites were predicted, which might be expressed and contributed to the broad-spectrum anti-infective activity. Three homologue members of the 24-membered macrocyclic lactone family, named as bacvalactones 1–3 bearing 13-O-ethyl (1); 15-O-furanyl-13-O-isobutyl-7-O-propyl-propanoate (2); and 15-O-furanyl-13-O-isobutyl-7-O-propyl-propanoate-7,24-dimethyl (3) functionalities, were acquired through bioactivity-guided purification. The macrocyclic lactones displayed bactericidal activity against opportunistic pathogens causing nosocomial infections, for instance, methicillin–resistant Staphylococcus aureus (MRSA), vancomycin–resistant Enterococcus faecalis (VREfs), and multidrug-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumonia with MIC ≤ 3.0 μg/mL, whereas standard antibiotics ampicillin and chloramphenicol were active only at concentrations of ≥ 6.25 mg/mL. The biosynthetic pathway of macrocyclic lactones that are generated by trans-AT polyketide synthases through stepwise extension of an acetyl starter unit by eleven sequential Claisen condensations with malonyl-CoA was established, and the structures were correlated with the gene organization of the mln operon, which encompasses nine genes mln A-I (approximately 47 kb in size). The best binding poses for each compounds (1–3) with Staphylococcus aureus peptide deformylase (SaPDF) unveiled docking scores (≥ 9.70 kcal/mol) greater than that of natural peptide deformylase inhibitors, macrolactin N and actinonin (9.14 and 6.96 kcal/mol, respectively), which supported their potential in vitro bioactivities. Thus, the present work demonstrated the potential of macrocyclic lactone for biotechnological and pharmaceutical applications against emerging multidrug-resistant pathogens.

Key Points

•Three antibacterial bacvalactones were identified from the symbiotic bacterium.

•The symbiotic bacterial genome was explored to identify the biosynthetic gene clusters.

•Trans-AT pks-assisted mln biosynthetic pathway of the macrocyclic lactone was proposed.

•In silico molecular interactions of the bacvalactones with S. aureus PDF were analyzed.

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Acknowledgments

The authors are thankful to the Indian Council of Agricultural Research (ICAR), New Delhi, for providing facilities to carry out the work. The authors thank the Director of Central Marine Fisheries Research Institute and Dean, Faculty of Marine Sciences, Lakeside Campus, Cochin University of Science and Technology, for support. Thanks are due to the Head of Marine Biotechnology Division, Central Marine Fisheries Research Institute, for facilitating research activities.

Funding

This work was supported by funding under the Kerala State Council for Science, Technology and Environment (grant number 040/FSHP-LSS/2014/KSCSTE) and Science and Engineering Research Board (SERB) Scheme (grant number SR/S1/OC-96A/2012) from the Department of Science and Technology, New Delhi, India.

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Author notes

  1. Kajal Chakraborty and Vinaya Kizhakkepatt Kizhakkekalam contributed equally to this work.

Authors and Affiliations

  1. Marine Bioprospecting Section of Marine Biotechnology Division, Central Marine Fisheries Research Institute, Ernakulam North, P.B. No. 1603, Cochin, India

    Kajal Chakraborty, Vinaya Kizhakkepatt Kizhakkekalam & Minju Joy

  2. Faculty of Marine Sciences, Lakeside Campus, Cochin University of Science and Technology, Cochin, Kerala State, India

    Vinaya Kizhakkepatt Kizhakkekalam

  3. Crustacean Fisheries Division, Central Marine Fisheries Research Institute, Ernakulam North, P.B. No. 1603, Cochin, India

    Rekha Devi Chakraborty

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  1. Kajal Chakraborty
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  2. Vinaya Kizhakkepatt Kizhakkekalam
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  3. Minju Joy
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  4. Rekha Devi Chakraborty
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Contributions

KC and VKK conceived and designed research, acquired funds, and conducted experiments. MJ analyzed data. RDC drafted the manuscript. All authors read and approved the manuscript.

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Correspondence to Kajal Chakraborty.

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Chakraborty, K., Kizhakkekalam, V.K., Joy, M. et al. Moving away from traditional antibiotic treatment: can macrocyclic lactones from marine macroalga-associated heterotroph be the alternatives?. Appl Microbiol Biotechnol 104, 7117–7130 (2020). https://doi.org/10.1007/s00253-020-10658-0

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