Dados do Trabalho

Título

Repositioning of drugs for the treatment of infections caused by the Mycobacterium abscessus subsp. abscessus

Introdução

Lung infections caused by Mycobacterium abscessus (Mab) are becoming increasingly prevalent around the world, especially in patients with cystic fibrosis, and their treatment is complex. Mab presents intrinsic and extrinsic resistance mechanisms that favors multidrug resistance to several known antibiotics. The long-term treatment favors severe toxic adverse effects resulting in treatment abandonment and generation of resistant bacteria, thus new drugs should be developed or screened from existing drugs to minimize adverse effects and to avoid resistance. For instance, drug repositioning is a rapid and economical alternative.

Objetivo(s)

Identify drugs with repositioning potential for the treatment of Mab lung infections

Material e Métodos

Using chemogenomics tools and public databases (Drugbank and Therapeutic Target Databases), Mab proteins were compared with therapeutic targets of suggested drugs and targets with similarity to Mab proteins were identified. As prioritization criteria, drugs with Log P >2, which were involved with the viability and pathogenicity were screened.

Resultados e Conclusão

We identified 446 suggested drugs for 594 Mab proteins with more than 30% similarity with known therapeutic targets. After the rational selection, 46 drugs with potential for repositioning in the treatment of Mab were selected, among which we have the furosemide, itraconazole, miconazole and ezetimibe. These findings are in consonance with publications that suggest that:i) furosemide exhibits bacteriostatic activity towards extracellular and intracellular M. bovis BCG; ii) itraconazole, could interact with other drugs used in the treatment of some non-tuberculous mycobacteria; iii) miconazole has significant antituberculosis activity against Mycobacterium tuberculosis (Mtb); iv) ezetimibe can be included in adjuvant therapy to reduce intracellular growth of Mtb.
Conclusions: These drugs may have activities against Mab or serve as scaffolds for the design and synthesis of structural analogues with greater potency, selectivity and permeability and, therefore, and are now being evaluated by molecular docking and in vitro activities.
Financing Agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq);

Palavras-chave

Drug repositioning; Mycobacterium abscessus; treatment; antimicrobial activity, virtual screening, chemogenomics, molecular docking.