Macozinone

The sustainable material, biochar (BC) from a hardwood source, was synthesized via pyrolysis process at 400 °C (BC400) and 700 °C (BC700) and used as a modifier during the electrochemical sensor design. The prepared BCs were characterized by scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET) analysis, and elemental analysis (CHNS). The development of rapid analytical techniques for detecting pesticides employing a low-cost carbon paste electrode (CPE) modified with BC is a novel strategy to provide a sensitive response to water pollution. The prepared working electrodes (unmodified CPE, BC400-CPE, and BC700-CPE) were compared for selected fungicides mancozeb (MCZ) and maneb (MAN) sensing, and BC700-CPE provides the most favorable analytical response of target analytes. Cyclic voltammetric investigations revealed that the electrode reaction is irreversible and controlled by the adsorption of MCZ and MAN at the surface of the BC700-CPE, which led to an optimization of the differential pulse adsorptive stripping voltammetric (DP-AdSV) method. The obtained working linear concentration ranges were 25-2780 μg L^-1 MCZ and 49-1840 μg L^-1 MAN in Britton-Robinson buffer pH 7.0 using CPE modified with 10 % BC700. The evaluated limit of detection was 7.5 μg L^-1 for MCZ and 15.0 μg L^-1 for MAN. Investigated interferences did not significantly affect the MCZ and MAN oxidation signal intensity. The developed DP-AdSV method was successfully applied to determine selected fungicides in spiked river water and wastewater samples, with good recovery and reproducibility.

Bedaquiline is the cornerstone of a new regimen for the treatment of drug-resistant tuberculosis. However, its clinical use is threatened by the emergence of bedaquiline-resistant strains of Mycobacterium tuberculosis . Bedaquiline targets mycobacterial ATP synthase but the predominant route to clinical bedaquiline resistance is via upregulation of the MmpS5L5 efflux pump due to mutations that inactivate the transcriptional repressor Rv0678 . Here, we show that the MmpS5L5 efflux pump reduces susceptibility to bedaquiline as well as its new, more potent derivative TBAJ-876 and other antimicrobial substrates, including clofazimine and the DprE1 inhibitors PBTZ-169 and OPC-167832. Furthermore, the increased resistance of Rv0678 mutants stems entirely from increased MmpS5L5 expression. These results highlight the potential of a pharmacological MmpS5L5 inhibitor to increase drug efficacy. Verapamil, primarily used as a calcium channel inhibitor, is known to inhibit diverse efflux pumps and to potentiate bedaquiline and clofazimine activity in M. tuberculosis . Here, we show that verapamil potentiates the activity of multiple diverse MmpS5L5 substrates. Using biochemical approaches, we demonstrate that verapamil does not exert this effect by acting as a disruptor of the protonmotive force used to power MmpS5L5, as previously proposed, suggesting that verapamil inhibits the function of the MmpS5L5 pump. Finally, norverapamil, the major verapamil metabolite, which has greatly reduced calcium channel activity, has equal potency in reducing resistance to MmpS5L5 substrates. Our findings highlight verapamil’s potential for enhancing bedaquiline TB treatment, for preventing acquired resistance to bedaquiline and other MmpS5L5 substrates, while also providing the impetus to identify additional MmpS5L5 inhibitors.