Activity of cefiderocol in combination with tetracycline analogues against carbapenem-resistant Acinetobacter baumannii
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Blue benzoquinone from scorpion venom shows bactericidal activity against drug-resistant strains of the priority pathogen Acinetobacter baumannii
Antibiotic-resistant bacteria pose a significant global health threat, particularly pathogens resistant to last-resort antibiotics, such as those listed as priority pathogens by the World Health Organization. Addressing this challenge requires the development of novel antimicrobial agents. Previously, we identified a blue 1,4-benzoquinone isolated from the venom of the Mexican scorpion Diplocentrus melici as a potent antimicrobial compound effective against Staphylococcus aureus and Mycobacterium tuberculosis. Moreover, we devised a cost-effective synthetic route for its production. In this study, we demonstrate that the blue benzoquinone exhibits antibacterial activity against additional pathogens, including the priority pathogen Acinetobacter baumannii. Notably, the compound effectively killed clinical strains of A. baumannii resistant to multiple antibiotics, including carbapenem and colistin. Furthermore, A. baumannii did not develop resistance to the benzoquinone even after multiple growth cycles under sub-inhibitory concentrations, unlike the tested antibiotics. These findings underscore the potential of this blue benzoquinone as a lead compound for the development of a new class of antibiotics targeting multidrug-resistant bacteria.
Exploration of vanoxerine analogues as antibacterial agents
Mycobacterium tuberculosis is a bacterial pathogen, responsible for approximately 1.3 million deaths in 2022 through tuberculosis infections. The complex treatment regimen required to treat tuberculosis and growing rates of drug resistance, necessitates the development of new anti-mycobacterial agents. One approach is to repurpose drugs from other clinical applications. Vanoxerine (GBR 12909) was previously shown to have anti-mycobacterial activity, through dissipating the membrane electric potential and hence, cellular energetics. Several vanoxerine analogues were synthesised in this study, which exhibited a range of activities against mycobacteria and enterococcus. All active analogues had similar impacts on the membrane electric potential and inhibition of ethidium bromide efflux. The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria.
Exploring BCL2 regulation and upstream signaling transduction in venetoclax resistance in multiple myeloma: potential avenues for therapeutic intervention
Investigating venetoclax (VTX) resistance in multiple myeloma (MM) is crucial for the development of novel therapeutic strategies to tackle resistance. We conducted a multi-omic characterization of established VTX-resistant isogenic human myeloma cell lines (HMCL) and primary MM patient samples pre- and post-VTX treatment. Transcriptomic and proteomic analysis revealed that resistance was largely associated with BCL-2 family protein dysregulation, including upregulation of anti-apoptotic proteins such as MCL-1, BCL-XL, BCL-2, and downregulation of pro-apoptotic members. Notably, the re-introduction of BIM into resistant cells restored VTX sensitivity and synergized with MCL-1 inhibitors. Upstream signaling pathways, including growth factor receptor tyrosine kinase (RTK) and phosphoinositide-3-kinase (PI3K) were implicated in this dysregulation. Simultaneous inhibition of MCL-1, BCL-XL, and upstream PI3K, RTK (FGF, EGF, and IGF1) mediated signaling enhanced VTX sensitivity. Post-translational modifications of MCL-1, particularly its stabilization via acetylation and phosphorylation, were investigated, although their inhibition only marginally increased VTX sensitivity. Lastly, the inhibition of AURKA and mitochondrial respiration also improved VTX sensitivity in some resistant HMCLs. Our findings suggest that combining VTX with MCL-1 and BCL-XL inhibitors or PIK3/RTK inhibitors holds potential for overcoming resistance. The study illustrates the importance of understanding molecular determinants of resistance to develop tailored therapeutic strategies.
Prevalence and transmission risk of colistin and multidrug resistance in long-distance coastal aquaculture
Due to the wide use of antibiotics, intensive aquaculture farms have been recognized as a significant reservoir of antibiotic resistomes. Although the prevalence of colistin resistance genes and multidrug-resistant bacteria (MDRB) has been documented, empirical evidence for the transmission of colistin and multidrug resistance between bacterial communities in aquaculture farms through horizontal gene transfer (HGT) is lacking. Here, we report the prevalence and transmission risk of colistin and multidrug resistance in 27 aquaculture water samples from 9 aquaculture zones from over 5000 km of subtropical coastlines in southern China. The colistin resistance gene mcr−1, mobile genetic element (MGE) intl1 and 13 typical antibiotic resistance genes (ARGs) were prevalent in all the aquaculture water samples. Most types of antibiotic (especially colistin) resistance are transmissible in bacterial communities based on evidence from laboratory conjugation and transformation experiments. Diverse MDRB were detected in most of the aquaculture water samples, and a strain with high-level colistin resistance, named Ralstonia pickettii MCR, was isolated. The risk of horizontal transfer of the colistin resistance of R. pickettii MCR through conjugation and transformation was low, but the colistin resistance could be steadily transmitted to offspring through vertical transfer. The findings have important implications for the future regulation of antibiotic use in aquaculture farms globally to address the growing threat posed by antibiotic resistance to human health.
Diurnal timing of physical activity in relation to obesity and diabetes in the German National Cohort (NAKO)
Physical activity supports weight regulation and metabolic health, but its timing in relation to obesity and diabetes remains unclear. We aimed to assess the diurnal timing of physical activity and its association with obesity and diabetes.
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