Bacterial siderophore mimicking iron complexes as DNA targeting antimicrobials

Boda, Sunil Kumar and Pandit, Subhendu and Garai, Aditya and Pal, Debnath and Basu, Bikramjit (2016) Bacterial siderophore mimicking iron complexes as DNA targeting antimicrobials. In: RSC ADVANCES, 6 (45). pp. 39245-39260.

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Abstract

Microbial secretion of siderophores for iron uptake can be employed as an efficient strategy to smuggle in bactericidal agents by conjugation to iron. Three iron complexes: complex 1Fe(L1)(2)] Cl-2 L1 = 3-(pyridin-2-yl)dipyrido3,2-a:2',3'-c]phenazine (pydppz or ligand 1), complex 2 Fe(BHA)(L2)Cl]Cl center dot H2O (BHA = benzohydroxamate) L2 = pyrenyl-dipicolylamine (pydpa or ligand 2) and complex 3 Fe(BHA)(L3)Cl]Cl center dot H2O L3 = phenyl-dipicolylamine (phdpa or ligand 3) were synthesized. The ligands were docked for binding to DNA and DNA polymerase I. The antibacterial efficacy of the iron complexes were evaluated against three pathogenic bacteria - Staphylococcus aureus (MRSA), Escherichia coli and Pseudomonas aeruginosa as well as cytotoxicity assessed in C2C12 mouse myoblast cells. In silico docking and molecular dynamic simulations of the ligands revealed stable and non-specific binding to DNA and DNA polymerase I, in the order: L1 > L2 > L3. The bactericidal effect of the iron complexes against MRSA predominantly occurred by bacterial DNA fragmentation as analyzed from gel electrophoresis and comet assay. The extent of DNA damage followed the order: complex 1 > complex 2 > complex 3, in commensurate with docking. Siderophore production elicited preferential bactericidal action of the iron complexes against MRSA. Both, complex 1 and complex 2 were 5-10 fold less toxic in C2C12 cells compared to MRSA. Taken together, a combination of DNA targeting and siderophore mimicking ligands conjugated to iron can be deployed as Trojan horse for the entry of antimicrobials into pathogenic bacteria. Thus, DNA targeting antimicrobials offer a promising solution to persistent bacterial infections. Their selectivity towards microbes can be promoted via siderophore uptake pathways.

Item Type:	Journal Article
Publication:	RSC ADVANCES
Publisher:	ROYAL SOC CHEMISTRY
Additional Information:	Copy right for this article belongs to the ROYAL SOC CHEMISTRY, THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND
Department/Centre:	Division of Chemical Sciences > Inorganic & Physical Chemistry Division of Chemical Sciences > Materials Research Centre Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering Division of Interdisciplinary Sciences > Computational and Data Sciences
Date Deposited:	15 Jun 2016 05:28
Last Modified:	11 Oct 2018 15:36
URI:	http://eprints.iisc.ac.in/id/eprint/53935

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