Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies, validated it by evaluating mixtures of laboratory parasite strains, and then used it to screen P. falciparum parasites from >1100 African infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally occurring K13-propeller variation. Although polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin-resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance.
Thiomicrospira(Tms) species are small sulfur-oxidizing chemolithoautotrophic members of the Gammaproteobacteria. Whilst the type species Tms. pelophila and closely related Tms. thyasirae exhibit canonical spiral morphology under sub-optimal growth conditions, most species are vibrios or rods. The 16S rRNA gene diversity is vast, with identities as low as 91.6 % for Tms. pelophila versus Tms. frisia, for example. Thiomicrospira was examined with closely related genera Hydrogenovibrio and Thioalkalimicrobium and, to rationalize organisms on the basis of the 16S rRNA gene phylogeny, physiology and morphology, we reclassify Tms. kuenenii, Tms. crunogena, Tms. thermophila and Tms. halophila to Hydrogenovibrio kuenenii comb. nov., H. crunogenus corrig. comb. nov., H. thermophilus corrig. comb. nov. and H. halophilus corrig. comb. nov. We reclassify Tms. frisia, Tms. arctica, Tms. psychrophila and Tms. chilensis to Thiomicrorhabdus (Tmr) gen. nov., as Tmr. frisia comb. nov., Tmr. arctica comb. nov., Tmr. psychrophila comb. nov. and Tmr. chilensis comb. nov. - the type species of Thiomicrorhabdus is Tmr. frisia. We demonstrate that Thioalkalimicrobium species fall within the genus Thiomicrospira sensu stricto, thus reclassifying them as Tms. aerophila corrig. comb. nov., Tms. microaerophila corrig. comb. nov., Tms. cyclica corrig. comb. nov. and Tms. sibirica corrig. comb. nov. We provide emended descriptions of the genera Thiomicrospira and Hydrogenovibrio and of Tms. thyasirae.
Tuberculosis, caused by the intracellular pathogen , is a deadly disease that requires a long course of treatment. The emergence of drug-resistant strains has driven efforts to discover new small molecules that can kill the bacterium. Here, we report characterizations of the compound HC2091, which kills in a time- and dose-dependent manner and inhibits growth in macrophages. Whole-genome sequencing of spontaneous HC2091-resistant mutants identified single-nucleotide variants in the mycolic acid transporter gene. HC2091-resistant mutants do not exhibit cross-resistance with the well-characterized membrane protein large 3 (MmpL3) inhibitor SQ109, suggesting a distinct mechanism of interaction with MmpL3. Additionally, HC2091 does not modulate bacterial membrane potential or kill nonreplicating , thus acting differently from other known MmpL3 inhibitors. RNA sequencing (RNA-seq) transcriptional profiling and lipid profiling of treated with HC2091 or SQ109 show that the two compounds target a similar pathway. HC2091 has a chemical structure dissimilar to those of previously described MmpL3 inhibitors, supporting the notion that HC2091 is a new class of MmpL3 inhibitor.
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