title: Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme.
abstract: The emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. Ribonucleotide reductase (RNR) is a key enzyme in DNA replication that acts by converting ribonucleotides into the corresponding deoxyribonucleotides, which are the building blocks of DNA replication and repair. RNR has been extensively studied as an ideal target for DNA inhibition, and several drugs that are already available on the market are used for anticancer and antiviral activity. However, the high toxicity of these current drugs to eukaryotic cells does not permit their use as antibacterial agents. Here, we present a radical scavenger compound that inhibited bacterial RNR, and the compound's activity as an antibacterial agent together with its toxicity in eukaryotic cells were evaluated. First, the efficacy of N-methyl-hydroxylamine (M-HA) in inhibiting the growth of different Gram-positive and Gram-negative bacteria was demonstrated, and no effect on eukaryotic cells was observed. M-HA showed remarkable efficacy against Mycobacterium bovis BCG and Pseudomonas aeruginosa. Thus, given the M-HA activity against these two bacteria, our results showed that M-HA has intracellular antimycobacterial activity against BCG-infected macrophages, and it is efficacious in partially disassembling and inhibiting the further formation of P. aeruginosa biofilms. Furthermore, M-HA and ciprofloxacin showed a synergistic effect that caused a massive reduction in a P. aeruginosa biofilm. Overall, our results suggest the vast potential of M-HA as an antibacterial agent, which acts by specifically targeting a bacterial RNR enzyme.
authors.affiliation: Departament de Genètica i de Microbiologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Julián
authors.affiliation: Institute for Bioengineering of Catalonia (IBEC), Bacterial infections and antimicrobial therapies; Baldiri Reixac 15-21, Barcelona, Spain.
authors.forename: Aida
authors.initials: A
authors.lastname: Baelo
authors.affiliation: Infectious Diseases Research Laboratory, Infectious Diseases Department, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Gavaldà
authors.affiliation: Institute for Bioengineering of Catalonia (IBEC), Bacterial infections and antimicrobial therapies; Baldiri Reixac 15-21, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Torrents
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D018441:Biofilms / Q000254:growth & development*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006898:Hydroxylamines / Q000494:pharmacology*; D009163:Mycobacterium bovis / Q000502:physiology*; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006898:Hydroxylamines; D012264:Ribonucleotide Reductases; C018338:N-methylhydroxylamine