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Mycobacterial carbonic anhydrases as targets for tuberculosis research

J Parkkinen(1) E Berrino(2) F Carta(2) M Hammarén(1) A Aspatwar(1) C Supuran(2) M Parikka(1) S Parkkila(1)

1:Tampere University; 2:University of Florence

Tuberculosis is amongst the deadliest infectious diseases worldwide with an annual caseload of over 10 million patients. World Health Organization estimates that within high-risk countries, one fifth of the patients develop resistance to at least one tuberculosis drug. The long-lasting anti-tuberculosis regimen burdens the healthcare system, and as the number of multi-drug resistant strains keeps rising, more robust treatment options are needed. One mechanism for developing anti-infectives is to find novel targets amongst the vital proteins of bacteria. A such option would be carbonic anhydrases, which exist in several structurally and functionally differing classes. Mycobacterial genomes encode for three β-carbonic anhydrases, enzymes believed having essential roles in Mycobacterium tuberculosis growth and virulence. Thus, the main aim of this research is to develop novel carbonic anhydrase inhibitors to enhance the treatment of tuberculosis when used in combination with first-line treatments. The research is carried out using Mycobacterium marinum, a natural pathogen of zebrafish and a well-established model organism for tuberculosis research. Currently, hundreds of carbonic anhydrase inhibitors have been screened against Mycobacterium marinum, revealing novel compounds that inhibit the metabolic activity and growth of bacteria even better than the first line drug rifampicin, whilst being safe to zebrafish larvae in toxicity modelling. Furthermore, several inhibitors have shown to possess bactericidal properties in Mycobacterium marinum biofilms. Two hits have been further tested in adult zebrafish infection model, showing subtle decrease in bacterial load. These results serve as a proof of concept for designing new anti-tubercular agents targeting the carbonic anhydrases.

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