Abstract
Mycobacterium tuberculosis is one of the most dangerous pathogens. Bacterial resistance to antituberculosis drugs grows each year, but searching for new drugs is a long process. Testing for available drugs to find active against mycobacteria may be a good alternative. In this work, antibiotics of the aureolic acid group were tested on a model organism Mycobacterium smegmatis. We presumed that antibiotics of this group may be potential G4 ligands. However, this was not confirmed in our analyses. We determined the antimicrobial activity of these drugs and revealed morphological changes in the cell structure upon treatment. Transcriptomic analysis documented increased expression of MSMEG_3743/soj and MSMEG_4228/ftsW, involved in cell division. Therefore, drugs may affect cell division, possibly disrupting the function of the Z-ring and the formation of a septum. Additionally, a decrease in the transcription level of several indispensable genes, such as nitrate reductase subunits (MSMEG_5137/narI and MSMEG_5139/narX) and MSMEG_3205/hisD was shown. We concluded that the mechanism of action of aureolic acid and its related compounds may be similar to that bedaquiline and disturb the NAD+/NADH balance in the cell. All of this allowed us to conclude that aureolic acid derivatives can be considered as potential antituberculosis drugs.
Highlights
IntroductionTuberculosis (TB) caused by Mycobacterium tuberculosis is still an acute problem worldwide
Tuberculosis (TB) caused by Mycobacterium tuberculosis is still an acute problem worldwide.The disease continues to take about a million lives every year [1]
It was shown that the well-known G4 ligands, TMPyP4 and BRACO-19, bind and stabilize G4 motifs and inhibit growth of M. tuberculosis
Summary
Tuberculosis (TB) caused by Mycobacterium tuberculosis is still an acute problem worldwide. The disease continues to take about a million lives every year [1]. The situation is complicated by the steady growth in a number of M. tuberculosis resistant strains. Multidrug and extensively drug-resistant tuberculosis pathogens are among them. An increasing number of strains resistant to all known antituberculosis drugs was witnessed in recent years [2,3]. The problem of development of new TB drugs is acute. Despite the fact that the numerous chemical libraries of synthetic and natural compounds have been exhaustively screened to identify new drugs, this process is arduous
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