Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme
Julián Gómez, Esther (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Baelo, Aida (Institut de Bioenginyeria de Catalunya)
Gavaldà, Joan (Hospital Universitari Vall d'Hebron)
Torrents Serra, Eduard (Institut de Bioenginyeria de Catalunya)

Data:	2015
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI10/01438 Ministerio de Economía y Competitividad BFU2011-24066 Ministerio de Economía y Competitividad ERA-Net Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-66 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1442 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-108
Nota:	This work was supported by grants from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III - PI10/01438), the European Regional Development Fund (FEDER), and the Generalitat de Catalunya (2009SGR-108) to EJ, and grants from the Spanish Ministry of Science and Innovation (Instituto de Salud Carlos III - PI081062), the European Regional Development Fund (FEDER),), the Spanish Ministerio de Ciencia e Innovación (BFU2011-24066), the ERA-NET PathoGenoMics, the Ramón y Cajal program and the Catalan and Spanish cystic fibrosis federation to ET.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Matèries del catàleg ; Methyl-hydroxylamine ; Antibacterial agents ; Ribonucleotide reductase ; RNR ; Paraules clau fora catàleg
Publicat a:	PloS one, Vol. 10, Issue. 3 (March 2015) , p. e0122049, ISSN 1932-6203

DOI: 10.1371/journal.pone.0122049
PMID: 25782003

Publicat 20 p, 8.9 MB

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