Actinobactérias da caatinga produtoras de antibióticos contra Mycobacterium tuberculosis: atividade, identificação molecular e metabolômica

Abstract

Tuberculosis (TB) is one of the leading causes of death from infectious diseases. Although TB is a curable and preventable disease, in 2023 approximately 10 million people developed TB, and an estimated 1.3 million deaths occurred worldwide. Despite some progress in research on new drug candidates, drug repurposing, and novel treatment regimens, there is still an urgent need for new drugs to treat TB, particularly due to the rising incidence of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains (MDR/XDR). Drug resistance poses a major challenge to the treatment and prevention of TB globally, making therapy more difficult, prolonged, and costly. Actinobacteria are Gram-positive bacteria known for producing a wide variety of bioactive metabolites, including antibiotics, immunosuppressants, and other medically relevant compounds. Among these, hundreds exhibit antimycobacterial activity and hold potential either as effective drugs or as starting points for the discovery of new agents against tuberculosis, with the genus Streptomyces standing out as one of the most important within this phylum, responsible for the production of a significant proportion of such molecules. In this context, the aim of this study was to isolate and characterize antimicrobial compounds active against M. tuberculosis derived from actinobacteria isolated from the Caatinga biome. Soil samples were collected, from which 340 actinobacterial strains were isolated. Of these, 19 (≈6%) demonstrated activity against an avirulent strain of M. tuberculosis (H37Ra). The metabolite profiles of these isolates were analyzed by LC-MS. Following chemical dereplication, compounds such as actinomycins molecules with previously known antimycobacterial activity were annotated. However, most of the compounds could not be identified by this technique. One isolate (I136), which exhibited prominent antimycobacterial activity and excellent in vitro growth, was selected for taxonomic, micromorphological, and in-depth chemical dereplication characterization. The isolate was examined using Gram staining and Scanning Electron Microscopy (SEM), and subsequently subjected to fermentation for secondary metabolite extraction. Gram staining revealed a Gram-positive bacterium with filamentous morphology, displaying long, branched filaments and spore formation. SEM analysis showed highly branched mycelia with well-defined spore chains arranged in a beaded pattern, characteristic of Streptomyces species. The metabolites produced by isolate I136 demonstrated antitubercular potential, with a MIC of 5 μg/mL against H37Ra. Chemical dereplication revealed that isolate I136 produces the metabolite neopyrrolomycin B, whose antimycobacterial activity has been previously reported in the literature. The data presented here reinforce the Caatinga as a valuable source of actinobacteria capable of producing bioactive metabolites against pathogens of high medical relevance, such as M. tuberculosis.