Biology subjects

Lungerich, B.

Publications and source records attributed to Lungerich, B..

3 recordsLinked to original sources

bioRxiv2026

3-Hydroxypropanamidines: from antiplasmodial leads to a novel antibacterial scaffold

Arylamino alcohols constitute an established class of antimalarial agents. While this class is best known for its potent antiplasmodial activity, selected members, most notably mefloquine, have also been reported to exhibit antibacterial activity. Structurally related 3-hydroxypropanamidines were developed as highly potent antimalarial agents. Here, we explored the antibacterial activity of three 3-hydroxypropanamidines (4 (BLK278), 5 (BLK280), and 6 (TKK088)) against clinically relevant Gram-positive and Gram-negative bacteria and investigated their cytotoxicity, in vitro pharmacokinetic properties, and proteome-based bacterial response to treatment. We observed good antibacterial activity against Staphylococcus aureus, with 6 (TKK088) displaying the highest activity against multidrug-resistant MRSA and VISA strains. 5 (BLK280) demonstrated the greatest spectrum of activity acting also against clinically relevant Gram-negative strains of Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella aerogenes, and Shigella sonnei. In cytotoxicity assays with HUVEC and HAOSMC cells, 4 (BLK278) and the previously reported 7 (TKK129) showed the most favourable overall profiles among the investigated 3-hydroxypropanamidines. The selectivity indices for S. aureus were below 2.5 with clear cell-type-dependent differences for all compounds including mefloquine, suggesting that improving antibacterial selectivity is an important objective for further optimization. In vitro pharmacokinetics showed high plasma protein binding and good human microsomal and plasma stability for all three 3-hydroxypropanamidines. Gel-based proteomic responses revealed a strong impact on the bacterial cell envelope. The observed acute proteomic responses reflect pleiotropic effects and are consistent with earlier reports implicating F0F1-ATPase as a potential molecular target of mefloquine in Streptococcus pneumoniae.

microbiology↗

bioRxiv2024

Small-molecule inhibitor of C-terminal HSP90 dimerization modulates autophagy and functions synergistically with mTOR inhibition to kill cisplatin-resistant cancer cells

BackgroundA major obstacle for the successful treatment of cancer is the primary presence or development of resistance mechanisms toward therapeutic intervention. In urothelial cancer, cisplatin-based regimens are still routinely employed, and multiple cellular pathways contribute to chemoresistance. Since the identification of heat shock protein 90 (HSP90) as potential cancer target, various HSP90 inhibitors (HSP90i) have been developed and evaluated in clinical trials. However, limited efficacy has been observed, mainly caused by dose-limiting toxicity and the concomitant induction of a cytoprotective heat shock response (HSR). To avoid this effect, inhibitors targeting the C-terminal domain (CTD) of HSP90 that do not elicit an HSR have been put forward. Additionally, the crosstalk between autophagy and HSP90 is currently being explored, since both processes work together in proteostasis, and the modulation of autophagic responses might be helpful in order to improve the efficacy of HSP90 inhibitors. MethodsThe second-generation small-molecule inhibitor VWK147 targeting HSP90 CTD dimerization was synthesized and characterized in detail by biochemical cell-free and cellular assays and molecular modeling. Specifically, HSP90 inhibition, cell viability, and autophagy were monitored in mono- and combined treatments. ResultsWe demonstrate that VWK147 induces cell death in both cisplatin-sensitive and cisplatin-resistant urothelial carcinoma cells. The treatment with VWK147 in these cells led to the destabilization of classical HSP90 client proteins without triggering an HSR. Additionally, we observe that VWK147 re-sensitizes resistant urothelial carcinoma cells to cisplatin and--in combination with mTOR inhibition--synergistically kills cisplatin-sensitive and -resistant cells, in contrast to what is observed upon treatment with the N-terminal domain-targeting HSP90 inhibitor 17-AAG. This synergy may be explained by VWK147-mediated inhibition of late autophagy events, and thus a blockade of autophagic flux. Finally, we also observed that VWK147 induces non-canonical LC3 lipidation, indicating that this compound possibly exerts a broader effect on ion balance or pH of the endolysosomal system. ConclusionVWK147 is a promising inhibitor that targets the C-terminal dimerization of HSP90 and simultaneously exhibits autophagy-modulating effects. This compound could potentially be an effective option for improving anti-cancer therapies and/or overcoming treatment resistance.

cell biology↗

bioRxiv2024

α-Aminooxyacetic acid derivatives acting as pro-drugs against Mycobacterium tuberculosis

Tuberculosis (TB), a significant cause of mortality globally, continues to claim 1.5 million lives each year. Despite recent advances in TB management, the emergence of multidrug-resistant strains of TB is exacerbating the treatment of TB. Therefore, there is an immediate necessity to uncover new anti-TB compounds with unprecedented targets. This study introduces novel antimycobacterial molecules that are based on -aminooxyacetic acid core structures. The lead compounds KSK-104 and KSK-106 displayed potent sub-micromolar antibacterial activity against Mycobacterium tuberculosis H37Rv and XDR clinical isolates, while exhibiting virtually no cytotoxicity against various human cells. Complementation experiments following whole genome sequencing of spontaneously resistant mutants generated against these bactericidal compounds suggested that they are pro-drugs that are intracellularly hydrolyzed by one or both of two specific amidohydrolases, Rv0552 and AmiC. Furthermore, proteomic and transcriptomic analyses of stressed cells and genetic interaction mapping employing transposon insertion sequencing suggest a "dirty drug" mechanism that involves the simultaneous attack of the various drug cleavage products on multiple intracellular targets. Our results suggest a primary role of the pyridoxal 5-phosphate (PLP) synthesis and salvage pathway and/or PLP-dependent enzymes, the oxidative stress network, and the largely uncharacterized Rv3092c-Rv3095 gene cluster in the mode of action.

microbiology↗