title: Amphotericin B and anidulafungin directly interact with DNA and induce oxidative damage in the mammalian genome.
abstract: Amphotericin B and anidulafungin are widely used antifungal drugs for the treatment of systemic and serious mycoses. Amphotericin B is a relatively toxic drug which has long been established. This study is first of its kind to systematically investigate the nature of binding to DNA, and to evaluate intercalation of AMP-B or ANIDULA with the aid of UV-Vis, ITC, and CD spectroscopy. The binding affinity of AMP-B with exclusion sites of 4.68 base pairs (1.2 × 10(5) M(-1)) was found to be higher than that of ANIDULA with exclusion sites of 6.67 base pairs (3.78 × 10(4) M(-1)); consistent with the binding affinity values obtained for AMP-B (10(5) M(-1)) and ANIDULA (10(4) M(-1)). The binding of two drugs with double-stranded DNA was favoured by negative enthalpy as well as negative entropy changes. The intercalation of drugs to duplex polynucleotide induced changes in the intrinsic CD spectra and revealed comparatively higher affinity towards AMP-B than ANIDULA. Molecular docking studies revealed that the negative binding energy was higher in the case of AMP-B reflecting more affinity towards single-stranded DNA. The results of the cytotoxicity, immunoblotting, and gene specific LA-QPCR assay have indicated that ANIDULA is less genotoxic than AMP-B. Hence, the superiority of ANIDULA over AMP-B as a systemic antifungal drug has been established beyond doubt.
authors.affiliation: Central Research Facility, Department of Chemistry, Indian Institute of Technology, Kharagpur, Kharagpur 721302, India. mandalsm@gmail.com.
authors.forename: Santi M
authors.initials: SM
authors.lastname: Mandal
authors.forename: Anirban
authors.initials: A
authors.lastname: Chakraborty
authors.forename: Maidul
authors.initials: M
authors.lastname: Hossain
authors.forename: Denial
authors.initials: D
authors.lastname: Mahata
authors.forename: William F
authors.initials: WF
authors.lastname: Porto
authors.forename: Ranadhir
authors.initials: R
authors.lastname: Chakraborty
authors.forename: Chinmay K
authors.initials: CK
authors.lastname: Mukhopadhyay
authors.forename: Octavio L
authors.initials: OL
authors.lastname: Franco
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Hazra
authors.forename: Amit
authors.initials: A
authors.lastname: Basak
mesh_terms: D000666:Amphotericin B / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000077612:Anidulafungin; D000818:Animals; D002151:Calorimetry; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D054714:Echinocandins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016678:Genome; D008322:Mammals; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D018384:Oxidative Stress; D013816:Thermodynamics
chemical_list: D054714:Echinocandins; D000666:Amphotericin B; D004247:DNA; D000077612:Anidulafungin