A Quinoxaline 1,4-Dioxide Activates DNA Repair Systems in : A Transcriptomic Study.

In 2022, the World Health Organization reported that tuberculosis (TB) was the second leading cause of death globally from a single infectious agent following COVID-19. The development of new antitubercular agents with novel mechanisms of action for use in complex TB therapy is considered a key approach to combating TB. In this study, we examined the gene expression profile of when exposed to a promising antituberculosis agent, quinoxaline 1,4-dioxide (QdNO) 7-chloro-2-(ethoxycarbonyl)-3-methyl-6-(piperazin-1-yl)quinoxaline-1,4-dioxide-1 (LCTA-3368).

Investigating the role of in intrinsic resistance to multiple drugs in .

Unlabelled: The increasing clinical significance of is owed to its innate high-level, broad-spectrum resistance to antibiotics and therefore rapidly evolves as an important human pathogen. This warrants the identification of novel targets for aiding the discovery of new drugs or drug combinations to treat infections. This study is inspired by the drug-hypersensitive profile of a mutant (U14) with transposon insertion in .

Novel Derivatives of Quinoxaline-2-carboxylic Acid 1,4-Dioxides as Antimycobacterial Agents: Mechanistic Studies and Therapeutic Potential.

The World Health Organization (WHO) reports that tuberculosis (TB) is one of the top 10 leading causes of global mortality. The increasing incidence of multidrug-resistant TB highlights the urgent need for an intensified quest to discover innovative anti-TB medications In this study, we investigated four new derivatives from the quinoxaline-2-carboxylic acid 1,4-dioxide class. New 3-methylquinoxaline 1,4-dioxides with a variation in substituents at positions 2 and 6(7) were synthesized via nucleophilic aromatic substitution with amines and assessed against a spp.

Kanamycin and Ofloxacin Activate the Intrinsic Resistance to Multiple Antibiotics in .

Drug resistance (DR) in is the main problem in fighting tuberculosis (TB). This pathogenic bacterium has several types of DR implementation: acquired and intrinsic DR. Recent studies have shown that exposure to various antibiotics activates multiple genes, including genes responsible for intrinsic DR.

Characterization of Genetic Variants Associated with Rifampicin Resistance Level in Clinical Isolates Collected in Guangzhou Chest Hospital, China.

Objective: Rifampicin (RIF)-resistance, a surrogate marker for multidrug-resistant tuberculosis (TB), is mediated by mutations in the gene. We aimed to investigate the prevalence of mutations pattern in the entire gene of clinical isolates and their association with resistance level to RIF.

Methods: Among 465 clinical isolates collected from the Guangzhou Chest Hospital, drug-susceptibility of 175 confirmed strains was performed via the proportion method and Bactec MGIT 960 system.

Arabinosyltransferase C Mediates Multiple Drugs Intrinsic Resistance by Altering Cell Envelope Permeability in Mycobacterium abscessus.

Mycobacterium abscessus is an emerging human pathogen leading to significant morbidity and even mortality, intrinsically resistant to almost all the antibiotics available and so can be a nightmare. Mechanisms of its intrinsic resistance remain not fully understood. Here, we selected and confirmed an M.

Synthesis and Characterization of Novel 2-Acyl-3-trifluoromethylquinoxaline 1,4-Dioxides as Potential Antimicrobial Agents.

The emergence of drug resistance in pathogens leads to a loss of effectiveness of antimicrobials and complicates the treatment of bacterial infections. Quinoxaline 1,4-dioxides represent a prospective scaffold for search of new compounds with improved chemotherapeutic characteristics. Novel 2-acyl-3-trifluoromethylquinoxaline 1,4-dioxides with alteration of substituents at position 2 and 6 were synthesized via nucleophilic substitution with piperazine moiety and evaluated against a broad panel of bacteria and fungi by measuring their minimal inhibitory concentrations.

Repurposing Based Identification of Novel Inhibitors against MmpS5-MmpL5 Efflux Pump of : A Combined In Silico and In Vitro Study.

In the current era of a pandemic, infections of COVID-19 and Tuberculosis (TB) enhance the detrimental effects of both diseases in suffering individuals. The resistance mechanisms evolving in are limiting the efficiency of current therapeutic measures and pressurizing the stressed medical infrastructures. The bacterial efflux pumps enable the development of resistance against recently approved drugs such as bedaquiline and clofazimine.

Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine, and Linezolid in a Murine Model of Tuberculosis.

TB47, a new drug candidate targeting QcrB in the electron transport chain, has shown a unique synergistic activity with clofazimine and forms a highly sterilizing combination. Here, we investigated the sterilizing effects of several all-oral regimens containing TB47 plus clofazimine and linezolid as a block and the roles of fluoroquinolones and pyrazinamide in them. All these regimens cured tuberculosis within 4 to 6 months in a well-established mouse model, and adding pyrazinamide showed a significant difference in bactericidal effects.

Identification of Mutations Conferring Tryptanthrin Resistance to .

Tuberculosis (TB), caused by , is a global burden, responsible for over 1 million deaths annually. The emergence and spread of drug-resistant strains (MDR-, XDR- and TDR-TB) is the main challenge in global TB-control, requiring the development of novel drugs acting on new biotargets, thus able to overcome the drug-resistance. Tryptanthrin is a natural alkaloid, with great therapeutic potential due to its simple way of synthesis and wide spectrum of biological activities including high bactericidal activity on both drug-susceptible and MDR strains.

Transcriptomic dataset of exposed to an imidazo[1,2-][1,2,4,5]tetrazine.

Deciphering the mechanism of action of novel anti-tuberculosis compounds is a key step in the drug development process. We have previously described a number of imidazo[1,2-][1,2,4,5]tetrazines with a promising activity on [1]. These compounds had predicted activity as serine‑threonine protein kinase inhibitors, however spontaneous drug resistant (formerly ) revealed only the mycobacterial mechanism of resistance to imidazo[1,2-][1,2,4,5]tetrazines: mutations in gene lead to overexpression of the operon in , thus providing resistance to imidazo[1,2-][1,2,4,5]tetrazines via enhanced efflux [2].

Transcriptional regulation of drug resistance mechanisms in Salmonella: where we stand and what we need to know.

Salmonellae have evolved a wide range of molecular mechanisms to neutralize the effect of antibiotics and evade the host immune system response. These mechanisms are exquisitely controlled by global and local regulators and enable the pathogens to use its energy as per need and hence allow the pathogen to economize the consumption of energy by its cellular machinery. Several families that regulate the expression of different drug resistance genes are known; some of these are: the TetR family (which affects tetracycline resistance genes), the AraC/XylS family (regulators that can act as both transcriptional activators and repressors), two-component signal transduction systems (e.

MmpS5-MmpL5 Transporters Provide Resistance to imidazo[1,2-][1,2,4,5]tetrazines.

The emergence and spread of drug-resistant strains (including MDR, XDR, and TDR) force scientists worldwide to search for new anti-tuberculosis drugs. We have previously reported a number of imidazo[1,2-][1,2,4,5]tetrazines - putative inhibitors of mycobacterial eukaryotic-type serine-threonine protein-kinases, active against . Whole genomic sequences of spontaneous drug-resistant mutants revealed four genes possibly involved in imidazo[1,2-][1,2,4,5]tetrazines resistance; however, the exact mechanism of resistance remain unknown.

Sequencing and Analysis of Three Mycobacterium tuberculosis Genomes of the B0/N-90 Sublineage.

We report the draft genome sequences of three isolates belonging to the B0/N-90 sublineage, EKB34, EKB53, and EKB79. The B0/N-90 sublineage belongs to the prevalent (in Russia) and highly virulent Beijing-B0/W148 sublineage. Isolates EKB34 and EKB79 were obtained from people with immune deficiency.

Synthesis and antimycobacterial activity of imidazo[1,2-b][1,2,4,5]tetrazines.

Tuberculosis (TB) has recently become the leading killer among infectious diseases. Multidrug and extensively drug-resistant Mycobacterium tuberculosis strains urge the need to develop anti-TB drugs with a novel mechanism of action. We describe synthesis of 22 novel imidazo[1,2-b][1,2,4,5]tetrazine derivatives with different substituents at C(3) and C(6) positions, and their antimycobacterial activity in vitro.

Draft Genome Sequences of 12 Strains Resistant to Imidazo[1,2-][1,2,4,5]Tetrazines.

Here, we report 12 draft genome sequences of mutant strains resistant to imidazo[1,2-][1,2,4,5]tetrazines, which are antituberculosis drug candidates. We have identified 7 different mutations in the MSMEG_1380 gene, which encodes the AcrR/TetR_N transcriptional repressor, which may activate efflux-mediated resistance.

Mutations in Efflux Pump Rv1258c (Tap) Cause Resistance to Pyrazinamide, Isoniazid, and Streptomycin in .

Although drug resistance in is mainly caused by mutations in drug activating enzymes or drug targets, there is increasing interest in the possible role of efflux in causing drug resistance. Previously, efflux genes have been shown to be upregulated upon drug exposure or implicated in drug resistance in overexpression studies, but the role of mutations in efflux pumps identified in clinical isolates in causing drug resistance is unknown. Here we investigated the role of mutations in efflux pump Rv1258c (Tap) from clinical isolates in causing drug resistance in We constructed point mutations V219A and S292L in Rv1258c in the chromosome of and the point mutations were confirmed by DNA sequencing.

Resistance to pyrazinamide in Russian Mycobacterium tuberculosis isolates: pncA sequencing versus Bactec MGIT 960.

Resistance to pyrazinamide (PZA) may impact clinical outcome of anti-tuberculosis chemotherapy. PZA susceptibility testing using MGIT 960 is not reliable and little information is available on the prevalence of PZA resistance in Russia. A collection of 64 clinical isolates of Mycobacterium tuberculosis, including 35 multidrug resistant and extensively drug-resistant (MDR/XDR), was analyzed for PZA resistance using MGIT 960, Wayne test, and sequencing of PZA resistance genes pncA, rpsA and panD.