Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme

PLoS One. 2015 Mar 17;10(3):e0122049. doi: 10.1371/journal.pone.0122049. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Biofilms / growth & development*
  • Enzyme Inhibitors / pharmacology
  • Hydroxylamines / pharmacology*
  • Mycobacterium bovis / physiology*
  • Pseudomonas aeruginosa / physiology*
  • Ribonucleotide Reductases / antagonists & inhibitors*

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Hydroxylamines
  • Ribonucleotide Reductases
  • N-methylhydroxylamine

Grants and funding

Funding provided by BFU2011-24066. Ministerio de Economia y Competitividad. Principal investigator: Dr. Eduard Torrents. 2009SGR66 and 2014SGR1442 from the Generalitat de Catalunya to Eduard Torrents. 2009SGR-108 from the Generalitat de Catalunya to Dr. Esther Julián. IIIPI10/01438 from the Instituto de Ivestigación Carlos III. Principal Investigator Dr. Esther Julián. ERA-Net pathogenomics from the Ministerio de Economia y Competitividad. Principal investigator: Dr. Eduard Torrents. Catalan and Spanish cystic foundation federations. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.