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Mycobacterium abscessus is a peculiar rapid-growing Mycobacterium (RGM) capable of surviving within eukaryotic cells thanks to an arsenal of virulence genes also found in slow-growing mycobacteria (SGM), such as Mycobacterium tuberculosis. A screen based on the intracellular survival in amoebae and macrophages (MΦ) of an M. abscessus transposon mutant library revealed the important role of MAB-0855, a yet uncharacterized Mycobacterial membrane protein Large (MmpL). Large-scale comparisons with SGM and RGM genomes uncovered MmpL12 proteins as putative orthologs of MAB-0855 and a locus-scale synteny between the MAB-0855 and Mycobacterium chelonae mmpL8 loci. A KO mutant of the MAB-0855 gene, designated herein as mmpL8MAB, had impaired adhesion to MΦ and displayed a decreased intracellular viability. Despite retaining the ability to block phagosomal acidification, like the WT strain, the mmpL8 mutant was delayed in damaging the phagosomal membrane and in making contact with the cytosol. Virulence attenuation of the mutant was confirmed in vivo by impaired zebrafish killing and a diminished propensity to induce granuloma formation. The previously shown role of MmpL in lipid transport prompted us to investigate the potential lipid substrates of MmpL8. Systematic lipid analysis revealed that MmpL8 was required for the proper expression of a glycolipid entity, a glycosyl diacylated nonadecyl diol (GDND) alcohol comprising different combinations of oleic and stearic acids. This study shows the importance of MmpL8 in modifying interactions between the bacteria and phagocytic cells and in the production of a previously unknown glycolipid family. [ABSTRACT FROM AUTHOR]

Antimalarial compounds ruthenoquine and methylruthenoquinewere studied by X-ray absorption spectroscopy both in solid stateand in solution, in normal (aqueous or CH2Cl2solutions) and oxidative (aqueous solution with H2O2, either equimolar or in large excess) conditions, to detectsmall changes in the coordination sphere of the ruthenium atom. Sincechanges in the EXAFS spectra of these compounds are quite subtle,a complete procedure was developed to assess the different sourcesof uncertainties in fitted structural parameters, including the useof multivariate statistic methods for simultaneous comparison of edgeenergy correction ΔE0and distances,which can take into account the very strong correlation between thesetwo parameters. Factors limiting the precision of distance determinationdepend on the recording mode. In transmission mode, the main sourceof uncertainty is the data reduction process, whereas in fluorescencemode, experimental noise is the main source of variability in thefitted parameters. However, it was shown that the effects of datareduction are systematic and almost identical for all compounds; hence,they can be ignored when comparing distances. Consequently, for bothfluorescence and transmission recorded spectra, experimental noiseis the limiting factor for distance comparisons, which leads to theuse of statistical methods for comparing distances. Univariate methods,focusing on the distance only, are shown to be less powerful in detectingchanges in distances than bivariate methods making a simultaneouscomparison of ΔE0and distances.This bivariate comparison can be done either by using the Hotelling’s T2test or by using a graphical comparison ofMonte Carlo simulation results. We have shown that using these methodsallows for the detection of very subtle changes in distances. Whenapplied to ruthenoquine compounds, it suggests that the implicationof the nonbinding doublet of the aminoquine nitrogen in either protonationor methylation enhances the tilt of the two cyclopentadienyls. Italso suggests that ruthenoquine and methylruthenoquine are, at leastpartially, oxidized in the presence of H2O2,with a small decrease in the Ru–C bond length and increasein the edge energy. [ABSTRACT FROM AUTHOR]

The article focuses on the Plasmodium falciparum (P. falciparum) apicolast drugs, particularly its role as potential target for malaria parasites. It explores the challenges in the search for apicolast drugs regarding its formulation in a bioavailable form, being administered orally, and passing all the pharmakinetic pitfalls. It highlights antibiotic drugs in the DNA replication in the apicoplast, transcription and RNA translation including ciprofloxacin, rifampicin, and doxycycline.

Non-tuberculous mycobacterium (NTM) infections, such as those caused by Mycobacterium abscessus , are increasing globally. Due to their intrinsic drug resistance, M. abscessus pulmonary infections are often difficult to cure using standard chemotherapy. We previously demonstrated that a piperidinol derivative, named PIPD1, is an efficient molecule both against M. abscessus and Mycobacterium tuberculosis , the agent of tuberculosis, by targeting the mycolic acid transporter MmpL3. These results prompted us to design and synthesize a series of piperidinol derivatives and to determine the biological activity against M. abscessus . Structure-activity relationship (SAR) studies pointed toward specific sites on the scaffold that can tolerate slight modifications. Overall, these results identified FMD-88 as a new promising active analogue against M. abscessus . Also, we determined the pharmacokinetics properties of PIPD1 and showed that intraperitoneal administration of this compound resulted in promising serum concentration and an elimination half-life of 3.2 hours., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Metal health: Ferroquine is a ferrocene-based analogue of the antimalarial drug chloroquine. In addition to the primary mechanism of quinoline action, fluorescent probe studies in infected red blood cells show another mechanism is at work. It is based on the production of HO(·) in the acidic and oxidizing environment of the digestive vacuole of the malaria parasite and implies that, with ferroquine, reinvasion can be inhibited., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L-fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking (3)E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100% inhibition of the proliferation of MDA-MB-231 cancer cells at 50 μM., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The aminoquinoline chloroquine (CQ) has been widely used for treating malaria since World War II. Resistance to CQ began to spread around 1957 and is now found in all malarious areas of the world. CQ resistance is caused by multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT). These mutations result in an increased efflux of CQ from the acidic digestive vacuole (DV) to the cytosol of the parasite. This year, we proposed a strategy to locate and quantify the aminoquinolines in situ within infected red blood cells (iRBCs) using synchrotron based X-ray nanoprobe fluorescence. Direct measurements of unlabeled CQ and ferroquine (FQ) (a ferrocene-CQ conjugate, extremely active against CQ-resistant strains) enabled us to evidence fundamentally different transport mechanisms from the cytosol to the DV between CQ and FQ in the CQ-susceptible strain HB3. These results inspired the present study of the localization of CQ and FQ in the CQ-resistant strain W2. The introduction of the ferrocene core in the lateral side chain of CQ has an important consequence: the transporter is unable to efflux FQ from the DV. We also found that resistant parasites treated by FQ accumulate a sulfur-containing compound, credibly glutathion, in their DV.

In 1996, the discovery of a relic chloroplast in Plasmodium and Toxoplasma cells has strongly changed our vision of these parasites in the "Tree of Life", and has opened an unexpected new field of investigation in the search for antiparasitic treatments, including antimalarials. This review details our current understanding of the sophisticated evolution of the parasites of the Apicomplexa phylum and briefly covers a decade of research and development in drug discovery, trying to target the malaria parasite at the level of its plant-like organelle. Fifteen years after the discovery of the apicoplast and ten years after the publication of the genome of Plasmodium falciparum, it seems that we have completed a first phase of tests of available antibiotics and herbicides. In the human host, the liver phase is the only parasitic stage, for which biological functions harbored by the apicoplast, such as fatty acid biosynthesis, seem indispensable. During the erythrocytic phase, recent results have focused the attention on the processes controlling the biogenesis of the apicoplast, and one of the functions harbored by the apicoplast, i.e. the biosynthesis of isoprenoids, as major -promising targets for future treatments., (© 2012 médecine/sciences – Inserm / SRMS.)