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 resistance.

The resistance mechanisms of bacteria against ciprofloxacin and new approaches for enhancing the efficacy of this antibiotic

“…It has also been demonstrated that ciprofloxacin, in addition to its effect on DNA gyrase, can cause reduction in the amount of DNA, RNA, and protein, as well as phospholipids, galactose, arabinose, glucosamine, and the mycolic acid of the M. smegmatis cell wall. However, these findings should be confirmed in the further studies (Figure 2) (11). Ciprofloxacin affects several Gram-positive bacteria such as Staphylococcus, Streptococcus, Enterococcus, Bacillus spp., and Mycobacterium.…”

Can We Arrest the Evolution of Antibiotic Resistance? The Differences between the Effects of Silver Nanoparticles and Silver Ions

“…Similarly, the induction of the SOS response and growth arrest were observed in P. aeruginosa treated with 0.12 mg/L CIP for 5 days; notably, the SOS response can lead to a 10- to 100-fold increase in persister cell levels. ,, In summary, P CIP cells developed CIP resistance by adopting various physiological strategies. Instantaneous targeted mutations (i.e., DNA gyrase) are possible and may play a role in CIP resistance.…”

“…Similarly, the induction of the SOS response and growth arrest were observed in P. aeruginosa treated with 0.12 mg/L CIP for 5 days; notably, the SOS response can lead to a 10-to 100-fold increase in persister cell levels. 19,22,23 Interestingly, the traits of P CIP/Ag + cells were similar to those of P CIP cells, and the selection mechanisms were the same because the bacteria developed similar detoxification mechanisms upon Ag + and CIP exposure. For example, bacteria undergoing anaerobic respiration utilize Ag + as terminal electron acceptors, thus reducing it to the particulate form, which diminishes its bioavailability and toxicity.…”

Antibacterial Activity of the Essential Oil From Litsea cubeba Against Cutibacterium acnes and the Investigations of Its Potential Mechanism by Gas Chromatography-Mass Spectrometry Metabolomics

“…It is worth noting that in C. acnes treated with EO, the abundance of these two unsaturated fatty acids 9-Octadecenoic acid and (9Z)-Hexadecenoic acid, main components of the cell wall and cell membrane, increased significantly, indicating that the synthesis and repair of the cell wall and cell membrane were strongly up-regulated ( Supplementary File 3 ). It has been shown in the literature that microorganisms would protect themselves by the increase of unsaturated fatty acids to avoid damage caused by the administration, which was a stress response ( Knoll et al, 2021 ). Therefore, it could be suggested that the damage of the EO to the cell wall and the cell membrane of the C. acnes may be indirectly caused by the influence of metabolism.…”