Elucidating the Antimycobacterial Mechanism of Action of Decoquinate Derivative RMB041 Using Metabolomics

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still remains one of the leading causes of death from a single infectious agent worldwide. The high prevalence of this disease is mostly ascribed to the rapid development of drug resistance to the current anti-TB drugs, exacerbated by lack of patient adherence due to drug toxicity. The aforementioned highlights the urgent need for new anti-TB compounds with different antimycobacterial mechanisms of action to those currently being used. An N-alkyl quinolone; decoquinate derivative RMB041, has recently shown promising antimicrobial activity against Mtb, while also exhibiting low cytotoxicity and excellent pharmacokinetic characteristics. Its exact mechanism of action, however, is still unknown. Considering this, we used GCxGC-TOFMS and well described metabolomic approaches to analyze and compare the metabolic alterations of Mtb treated with decoquinate derivative RMB041 by comparison to non-treated Mtb controls. The most significantly altered pathways in Mtb treated with this drug include fatty acid metabolism, amino acid metabolism, glycerol metabolism, and the urea cycle. These changes support previous findings suggesting this drug acts primarily on the cell wall and secondarily on the DNA metabolism of Mtb. Additionally, we identified metabolic changes suggesting inhibition of protein synthesis and a state of dormancy

Elucidating the antimycobacterial mechanism of action of ciprofloxacin using metabolomics

In the interest of developing more effective and safer anti-tuberculosis drugs, we used a GCxGC-TOF-MS metabolomics research approach to investigate and compare the metabolic profiles of Mtb in the presence and absence of ciprofloxacin. The metabolites that best describe the differences between the compared groups were identified as markers characterizing the changes induced by ciprofloxacin. Malic acid was ranked as the most significantly altered metabolite marker induced by ciprofloxacin, indicative of an inhibition of the tricarboxylic acid (TCA) and glyoxylate cycle of Mtb. The altered fatty acid, myo-inositol, and triacylglycerol metabolism seen in this group supports previous observations of ciprofloxacin action on the Mtb cell wall. Furthermore, the altered pentose phosphate intermediates, glycerol metabolism markers, glucose accumulation, as well as the reduction in the glucogenic amino acids specifically, indicate a flux toward DNA (as well as cell wall) repair, also supporting previous findings of DNA damage caused by ciprofloxacin. This study further provides insights useful for designing network whole-system strategies for the identification of possible modes of action of various drugs and possibly adaptations by Mtb resulting in resistance.https://www.mdpi.com/journal/microorganismsam2022Plant Production and Soil Scienc

Elucidating the Antimycobacterial Mechanism of Action of Ciprofloxacin Using Metabolomics

Abstract: In the interest of developing more effective and safer anti-tuberculosis drugs, we used a GCxGC-TOF-MS metabolomics research approach to investigate and compare the metabolic profiles of Mtb in the presence and absence of ciprofloxacin. The metabolites that best describe the differences between the compared groups were identified as markers characterizing the changes induced by ciprofloxacin. Malic acid was ranked as the most significantly altered metabolite marker induced by ciprofloxacin, indicative of an inhibition of the tricarboxylic acid (TCA) and glyoxylate cycle of Mtb. The altered fatty acid, myo-inositol, and triacylglycerol metabolism seen in this group supports previous observations of ciprofloxacin action on the Mtb cell wall. Furthermore, the altered pentose phosphate intermediates, glycerol metabolism markers, glucose accumulation, as well as the reduction in the glucogenic amino acids specifically, indicate a flux toward DNA (as well as cell wall) repair, also supporting previous findings of DNA damage caused by ciprofloxacin. This study further provides insights useful for designing network whole-system strategies for the identification of possible modes of action of various drugs and possibly adaptations by Mtb resulting in resistanc

Evaluation of <em>Pseudomonas fulva</em> PS9.1 and <em>Bacillus velezensis</em> NWUMFkBS10.5 as Candidate Plant Growth Promoters during Maize-<em>Fusarium</em> Interaction

Based on in vitro assessments, molecular and chemical analysis, Pseudomonas fulva PS9.1 and Bacillus velezensis NWUMFkBS10.5 are candidate biocontrol agents for plant disease management including maize fusariosis, a disease caused by members of the Fusarium species. This in vivo study evaluated the bio-protective potential of the aforementioned rhizobacteria strains on maize against the proliferation of the pathogenic fungus Fusarium graminearum (Fg). The study results show that the bacterized plants were not susceptible to Fg aggression and the antagonists displayed the capability to proliferate in the presence of other likely competing microflora. The screen-house data also suggest that the presence of resident soil microbiota impacted the activity of antagonists (PS9.1 and NWUMFkBS10.5). This variation was recorded in the soil treatments (sterilized and unsterilized soil). In all the experimental periods, bacterized maize plants with or without Fg inoculation significantly (p = 0.05) grew better in unsterilized soil. Besides, during the experimental periods, all the consortia treatments with or without Fg infection regardless of the soil used demonstrated appreciable performance. The result of this study suggests that the microbial agents can actively colonize the surface of their maize plant host, improve plant growth, and suppress the growth of phytopathogens. Considering their overall performance in this screen-house evaluation, P. fulva PS9.1 and B. velezensis NWUMFkBS10.5 have potential for field applications. All safety issues regarding their use under field conditions and risks associated with their extended-release into the environmental will, however, be assessed prior to further bioformulation, field investigation, and scale-up

Genomic exploration of Bacillus thuringiensis MORWBS1.1 - candidate biocontrol agent,predicts genes for biosynthesis of zwittermicin, 4,5-DOPA dioxygenase extradiol, and quercetin 2,3-dioxygenase

Many strains fromBacillus thuringiensisare known for theirgenomic robustness and antimicrobial potentials. As a result, thequest for their biotechnological applications, especially in theagroindustry (e.g., as biopesticides), has increased over the years.This study documents the genome sequencing and probing of aFusariumantagonist (B.thuringiensisstrain MORWBS1.1) withpossible biopesticidal metabolite producing capacity from SouthAfrica. Based on in vitro evaluation and in silico antiSMASHinvestigation,B.thuringiensisstrain MORWBS1.1 exhibited dis-tinctive genomic properties that could be further exploited for inplanta and food additive production purposes

Elucidating the antimycobacterial mechanism of action of ciprofloxacin using metabolomics

In the interest of developing more effective and safer anti-tuberculosis drugs, we used a GCxGC-TOF-MS metabolomics research approach to investigate and compare the metabolic profiles of Mtb in the presence and absence of ciprofloxacin. The metabolites that best describe the differences between the compared groups were identified as markers characterizing the changes induced by ciprofloxacin. Malic acid was ranked as the most significantly altered metabolite marker induced by ciprofloxacin, indicative of an inhibition of the tricarboxylic acid (TCA) and glyoxylate cycle of Mtb. The altered fatty acid, myo-inositol, and triacylglycerol metabolism seen in this group supports previous observations of ciprofloxacin action on the Mtb cell wall. Furthermore, the altered pentose phosphate intermediates, glycerol metabolism markers, glucose accumulation, as well as the reduction in the glucogenic amino acids specifically, indicate a flux toward DNA (as well as cell wall) repair, also supporting previous findings of DNA damage caused by ciprofloxacin. This study further provides insights useful for designing network whole-system strategies for the identification of possible modes of action of various drugs and possibly adaptations by Mtb resulting in resistance.https://www.mdpi.com/journal/microorganismsam2022Plant Production and Soil Scienc

Elucidating the antimycobacterial mechanism of action of ciprofloxacin using metabolomics

In the interest of developing more effective and safer anti-tuberculosis drugs, we used a GCxGC-TOF-MS metabolomics research approach to investigate and compare the metabolic profiles of Mtb in the presence and absence of ciprofloxacin. The metabolites that best describe the differences between the compared groups were identified as markers characterizing the changes induced by ciprofloxacin. Malic acid was ranked as the most significantly altered metabolite marker induced by ciprofloxacin, indicative of an inhibition of the tricarboxylic acid (TCA) and glyoxylate cycle of Mtb. The altered fatty acid, myo-inositol, and triacylglycerol metabolism seen in this group supports previous observations of ciprofloxacin action on the Mtb cell wall. Furthermore, the altered pentose phosphate intermediates, glycerol metabolism markers, glucose accumulation, as well as the reduction in the glucogenic amino acids specifically, indicate a flux toward DNA (as well as cell wall) repair, also supporting previous findings of DNA damage caused by ciprofloxacin. This study further provides insights useful for designing network whole-system strategies for the identification of possible modes of action of various drugs and possibly adaptations by Mtb resulting in resistance.https://www.mdpi.com/journal/microorganismsam2022Plant Production and Soil Scienc