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The treatment of Mycobacterium avium infections is still long, complex, and often poorly tolerated, besides emergence of resistances. New active molecules that are more effective and better tolerated are deeply needed. Mefloquine and its enantiomers ((+) Erythro-mefloquine ((+)-EMQ) and (-)-Erythro-mefloquine ((-)-EMQ)) have shown efficacy in both in vitro and in vivo, in a mouse model of M. avium intraveinous infection. However, no study reports aerosol model of infection or combination with gold standard treatment. That was the aim of our study. In an aerosol model of M. avium infection in BALB/c mice, we used five treatment groups as followed: Clarithromycin-Ethambutol-Rifampicin (CLR-EMB-RIF, standard of care, n = 15), CLR-EMB-MFQ (n = 15), CLR-EMB-(+)-EMQ (n = 15), CLR-EMB-(-)-EMQ (n = 15) and an untreated group (n = 25). To evaluate drug efficacy, we sacrificed each month over 3 months, 5 mice from each group. Lung homogenates were diluted and plated for colony forming unit count (CFU) expressed in Log10. At each time point, we found a significant difference between the untreated group and each of the treatment groups (p<0.005). The (+)-EMQ-CLR-EMB group was the group with the lowest CFU count at each time point but never reached statistical significance. The results of each group 3 months after treatment are: (+)-EMQ-CLR-EMB (4.43 ± 0.26), RIF-CLR-EMB (4.83 ± 0.37), (-)-EMQ-CLR-EMB (4.82 ± 0.18), MFQ-CLR-EMB (4.70 ± 0.21). In conclusion, MFQ and its enantiomers appear to be as effective as rifampicin in combination therapy. Further studies are needed to evaluate the ability of these drugs to prevent selection of clarithromycin resistant strains and potential for lung sterilization. [ABSTRACT FROM AUTHOR]

By taking into account our previously described series of 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds, we have now designed, prepared, and evaluated in vitro against Plasmodium falciparum a novel series of structural analogues of these molecules, i.e., the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives. The pharmacological data showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new nitrogen polyphenoxymethylbenzene compounds was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivative 1m was found as one of the most potent and promising antimalarial candidates with favorable cytotoxic to antiprotozoal properties in the P. falciparum strains W2 and 3D7. In conclusion, this 1,3,5-tris[(4-(pyridin-3-ylmethylaminomethyl)phenoxyl)methyl]benzene 1m (IC50 = 0.07 μM on W2, 0.06 μM on 3D7, and 62.11 μM on HepG2) was identified as the most promising antimalarial derivative with selectivity indexes (SI) of 887.29 on the W2 P. falciparum chloroquine-resistant strain, and of 1035.17 on the chloroquine-sensitive and mefloquine decreased sensitivity strain 3D7. It has been previously described that the telomeres of P. falciparum could represent potential targets for these types of polyaromatic compounds; therefore, the capacity of our novel derivatives to stabilize the parasitic telomeric G-quadruplexes was assessed using a FRET melting assay. However, with regard to the stabilization of the protozoal G-quadruplex, we observed that the best substituted derivatives 1, which exhibited some interesting stabilization profiles, were not the most active antimalarial compounds against the two Plasmodium strains. Thus, there were no correlations between their antimalarial activities and selectivities of their respective binding to G-quadruplexes. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is a critical public health issue. Among the multi-drug resistant microorganisms in question, Pseudomonas aeruginosa has been designated by the WHO as a priority threat. Its virulence is orchestrated through quorum sensing (QS). This sophisticated communication network relies on the release and perception of autoinducers acting as population density indicators. Therefore, the interest of a quorum silencing pharmacological approach has unfolded to quench bacterial pathogenicity without impairing growth. In this article, we reported the development of a family of indazole–quinolone hybrids as anti-virulence agents. These new biaromatic compounds were designed as potential specific QS quenchers against P. aeruginosa. Our transdisciplinary research methodology included their synthesis using palladocatalyzed cross-coupling reactions, as well as their in silico physicochemical and in vitro biological evaluation. The hit 7-chloro-2-indazolyl-4-quinolone Ie shows a promising anti-biofilm and anti-pyocyanin efficiency (35% inhibition at 25 µM and 35% inhibition at 100 µM, respectively) without an anti-pseudomonal bacteriostatic effect. It also demonstrated a moderate eukaryotic cytotoxicity. Its anti-QS properties have been investigated using metabolomic and molecular modelling studies. [ABSTRACT FROM AUTHOR]

A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay. [ABSTRACT FROM AUTHOR]

Resistance to antimicrobial drugs is currently a serious threat to human health. Consequently, we are facing an urgent need for new antimicrobial drugs acting with original modes of action. The ubiquitous and widely conserved microbial fatty acid biosynthesis pathway, called FAS-II system, represents a potential target to tackle antimicrobial resistance. This pathway has been extensively studied, and eleven proteins have been described. FabI (or InhA, its homologue in mycobacteria) was considered as a prime target by many teams and is currently the only enzyme with commercial inhibitor drugs: triclosan and isoniazid. Furthermore, afabicin and CG400549, two promising compounds which also target FabI, are in clinical assays to treat Staphylococcus aureus. However, most of the other enzymes are still underexploited targets. This review, after presenting the FAS-II system and its enzymes in Escherichia coli, highlights the reported inhibitors of the system. Their biological activities, main interactions formed with their targets and structure–activity relationships are presented as far as possible. [ABSTRACT FROM AUTHOR]

Objective: The phytochemical composition and the antibacterial and antifungal properties of Zizyphus lotus L. (ZL) leaves and Ruta chalepensis L. (RC) aerial parts harvested from Oran in northwest Algeria were assessed against multidrug-resistant (MDR) clinical pathogens. Materials and Methods: The phenolic compounds identification in the hydromethanolic (MeOH.E) and the aqueous extracts (Aq. E) was done by HPLC-DAD analysis, while the phenolic, flavonoid and tannin contents were determined using quantitative methods. The antibacterial and antifungal activities were also determined. The synergistic effect between both plants was elucidated using the checkerboard dilution test. Results: An important phenolic content was determined with higher concentrations in Z. lotus leaves extracts than R. chalepensis. The HPLC-DAD analysis allowed us to identify benzoic acid as the major phenolic compound in Z. lotus extracts, while catechin, quercetin and epicatechin were the major compounds identified in R. chalepensis. Important antimicrobial activity was observed against all the clinical pathogen strains. The most potent effect was estimated against MDR Salmonella enterica sp. arizonae with 20±0.1mm of growth inhibition zone diameter using RCMeOH.E, while a diameter of 35.03±0.06 mm was measured using ZLMeOH.E. Also, important anti-Candida activity was estimated. No synergistic interaction against the different microbial strains was determined by applying the combinations of both plants' extracts, with a fractional inhibitory concentration index superior to 4 (FICindex >4). Conclusion: Z. lotus and R. chalepensis can be exploited in the medical field as a potential source of antimicrobial components. [ABSTRACT FROM AUTHOR]

Despite efforts to understand and treat acute myeloid leukemia (AML), there remains a need for more comprehensive therapies to prevent AML-associated relapses. To identify new therapeutic strategies for AML, we [...]