title: Unique structural features in DNA polymerase IV enable efficient bypass of the N2 adduct induced by the nitrofurazone antibiotic.
abstract: The reduction in the efficacy of therapeutic antibiotics represents a global problem of increasing intensity and concern. Nitrofuran antibiotics act primarily through the formation of covalent adducts at the N(2) atom of the deoxyguanosine nucleotide in genomic DNA. These adducts inhibit replicative DNA polymerases (dPols), leading to the death of the prokaryote. N(2)-furfuryl-deoxyguanosine (fdG) represents a stable structural analog of the nitrofuran-induced adducts. Unlike other known dPols, DNA polymerase IV (PolIV) from E. coli can bypass the fdG adduct accurately with high catalytic efficiency. This property of PolIV is central to its role in reducing the sensitivity of E. coli toward nitrofuran antibiotics such as nitrofurazone (NFZ). We present the mechanism used by PolIV to bypass NFZ-induced adducts and thus improve viability of E. coli in the presence of NFZ. Our results can be used to develop specific inhibitors of PolIV that may potentiate the activity of nitrofuran antibiotics.
authors.affiliation: National Centre for Biological Sciences (NCBS-TIFR), GKVK Campus, Bellary Road, Bangalore 560065, India; Manipal University, Manipal.edu, Madhav Nagar, Manipal 576104, India.
authors.forename: Jithesh
authors.initials: J
authors.lastname: Kottur
authors.affiliation: National Centre for Biological Sciences (NCBS-TIFR), GKVK Campus, Bellary Road, Bangalore 560065, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
authors.forename: Kiran R
authors.initials: KR
authors.lastname: Gore
authors.affiliation: National Centre for Biological Sciences (NCBS-TIFR), GKVK Campus, Bellary Road, Bangalore 560065, India; Manipal University, Manipal.edu, Madhav Nagar, Manipal 576104, India.
authors.forename: Naveen
authors.initials: N
authors.lastname: Narayanan
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
authors.forename: Biswajit
authors.initials: B
authors.lastname: Samanta
authors.affiliation: Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India. Electronic address: pradeep@chem.iitb.ac.in.
authors.forename: Pushpangadan I
authors.initials: PI
authors.lastname: Pradeepkumar
authors.affiliation: Regional Centre for Biotechnology, 180, Udyog Vihar, Phase 1, Gurgaon 122016, India; National Centre for Biological Sciences (NCBS-TIFR), GKVK Campus, Bellary Road, Bangalore 560065, India. Electronic address: deepak@rcb.res.in.
authors.forename: Deepak T
authors.initials: DT
authors.lastname: Nair
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000737:chemistry* / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009583:Nitrofurazone / Q000494:pharmacology*; D017672:Nitrogen Compounds / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D026361:Reactive Nitrogen Species / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D017672:Nitrogen Compounds; D026361:Reactive Nitrogen Species; D019951:DNA Polymerase beta; D009583:Nitrofurazone