Staff member

Aida Baelo Álvarez

PhD Student
Bacterial Infections: Antimicrobial Therapies
+34 934 034 678
Staff member publications

Baelo, Aida, Julián, Esther, Torrents, Eduard, (2016). Methyl-hydroxylamine specifically inhibits ribonucleotide reductase activity in pathogenic bacteria New Biotechnology Biotech Annual Congress (BAC 2015) , Elsevier (Salamanca, Spain) 33, (3), 417

Infectious diseases constitute a tenacious and major public-health problem all over the world; the emergence and increasing prevalence of multi-drug resistant bacteria demand the discovery of new therapeutic approaches. Bacterial DNA synthesis opens new horizons in the discovery of new antibacterial targets due to remarkable differences to the eukaryotic system. During the course of an infection, a great number of bacteria need to multiply inside the body and, for that, active DNA synthesis with a balanced supply of deoxyribonucleotides (dNTPs) is required. RiboNucleotide Reductase (RNR) is the key enzyme that provides the nucleotide precursors for DNA replication and repair. This enzyme is a suitable target candidate for bacterial growth inhibition. In this work we have firstly identified the radical scavenger methyl-hydroxylamine (M-HA) as an efficacious antimicrobial agent that inhibits gram-negative and gram-positive pathogenic bacteria, targeting the RNR enzyme. Later, we have focused our work studying the ability of M-HA to inhibit the intracellular growth of Mycobacteria in macrophages, and the formation of Pseudomonas aeruginosa biofilms.

Torrents, E., Baelo, Aida, Levato, R., Julián, E., Crespo, Anna, Astola, Josep, Gavaldà, J., Engel, E., Mateos-Timoneda, M.A., (2016). Mejora en la administración antibiotic para el tratamiento de infecciones en forma de biofilm con el uso de nanopartículas que disgregan la matriz extracellular Enfermedades Infecciosas y Microbiología Clínica XX Congreso de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) , Elsevier (Barcelona, Spain) 34, (SE1), 31

Las infecciones causadas por bacterias formadoras de biopelículas o biofilms son una amenaza importante para los pacientes hospitalizados y suponen la principal causa de infecciones crónicas, como las producidas en la enfermedad pulmonar obstructiva crónica (EPOC) y la fibrosis quística. Existe una necesidad urgente de desarrollar nuevos antibióticos o nuevos enfoques terapéuticos que permitan el tratamiento de este tipo de infecciones ya que los antibióticos convencionales no logran eliminar las bacterias que están formando biofilms

Baelo, Aida, Levato, Riccardo, Julián, Esther, Crespo, Anna, Astola, José, Gavaldà, Joan, Engel, Elisabeth, Mateos-Timoneda, Miguel Angel, Torrents, Eduard, (2015). Disassembling bacterial extracellular matrix with DNase-coated nanoparticles to enhance antibiotic delivery in biofilm infections Journal of Controlled Release 209, 150-158

Abstract Infections caused by biofilm-forming bacteria are a major threat to hospitalized patients and the main cause of chronic obstructive pulmonary disease and cystic fibrosis. There is an urgent necessity for novel therapeutic approaches, since current antibiotic delivery fails to eliminate biofilm-protected bacteria. In this study, ciprofloxacin-loaded poly(lactic-co-glycolic acid) nanoparticles, which were functionalized with DNase I, were fabricated using a green-solvent based method and their antibiofilm activity was assessed against Pseudomonas aeruginosa biofilms. Such nanoparticles constitute a paradigm shift in biofilm treatment, since, besides releasing ciprofloxacin in a controlled fashion, they are able to target and disassemble the biofilm by degrading the extracellular DNA that stabilize the biofilm matrix. These carriers were compared with free-soluble ciprofloxacin, and ciprofloxacin encapsulated in untreated and poly(lysine)-coated nanoparticles. DNase I-activated nanoparticles were not only able to prevent biofilm formation from planktonic bacteria, but they also successfully reduced established biofilm mass, size and living cell density, as observed in a dynamic environment in a flow cell biofilm assay. Moreover, repeated administration over three days of DNase I-coated nanoparticles encapsulating ciprofloxacin was able to reduce by 95% and then eradicate more than 99.8% of established biofilm, outperforming all the other nanoparticle formulations and the free-drug tested in this study. These promising results, together with minimal cytotoxicity as tested on J774 macrophages, allow obtaining novel antimicrobial nanoparticles, as well as provide clues to design the next generation of drug delivery devices to treat persistent bacterial infections.

Keywords: Pseudomonas aeruginosa, Biofilm, Ciprofloxacin, DNase I, Nanoparticles

Julián, E., Baelo, A., Gavaldà, J., Torrents, E., (2015). Methyl-hydroxylamine as an efficacious antibacterial agent that targets the ribonucleotide reductase enzyme PLoS ONE 10, (3), e0122049

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.

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