Biology subjects

Jirgensons, A.

Publications and source records attributed to Jirgensons, A..

3 recordsLinked to original sources

bioRxiv2026

Discovery of P1-P2 depeptidized boronic acid based Plasmodium falciparum SUB1 inhibitor

The Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is an essential enzyme required for parasite egress from host red blood cells and represents a promising target for antimalarial drugs. Peptidic boronic acids are potent reported PfSUB1 inhibitors, however their drug-likeness is limited by their pronounced peptidic character. Based on molecular docking studies using peptidic boronic acids, we designed a series of partially depeptidized PfSUB1 inhibitors by replacing the P1-P2 dipeptide fragment with a 3-aminomethylphenylboronic acid core. Structure-activity relationship (SAR) investigations targeting interaction with active-site residue Lys138 revealed that introducing a meta-carboxylate group (compound 3a) markedly enhanced inhibitory activity, yielding a low-nanomolar PfSUB1 inhibitor (IC50= 10.2 nM). Bioisosteric replacement of the carboxylic acid demonstrated that an N-acylsulfonamide group (compound 4k) retained high enzymatic potency (IC50= 13.5 nM)). In cellular assays against blood-stage P. falciparum (3D7 strain), the leading depeptidized boronic acids exhibited growth inhibition with values in the low-micromolar range suggesting that further structural modifications are needed to enhance membrane permeability across host and parasite membranes to reach exonemes prior to egress. Overall, this study validates the P1-P2 depeptidization of boronic acid scaffolds and provides key SAR insights for the rational design of non-peptidic PfSUB1-targeted antimalarials.

pharmacology and toxicology↗

bioRxiv2025

Disassembly of the Escherichia coli AcrABZ-TolC efflux pump by ligand-mediated disruption of TolC-AcrA interfacial contacts

The outer membrane factor TolC is an essential component of various efflux pump complexes in E. coli and represents a potential target for antibiotic adjuvants. By means of a virtual screen for TolC-binding compounds, we identified the kinase inhibitor CEP- 37440 to shift the minimum inhibitory concentration of antibiotics piperacillin and levofloxacin in E. coli. To determine the substructure relevant for TolC binding, a hit deconstruction approach was applied, resulting in a fragment-like compound with low affinity for TolC and AcrB (LP-115). Dynamic light scattering revealed LP-115 to reduce the hydrodynamic radius of AcrABZ-TolC, indicating a disassembly of the efflux pump complex. A cryo-EM structure demonstrated LP-115 to bind at the TolC-AcrA interface within the AcrABZ-TolC complex, thereby disordering the interface and inducing a closed conformation of TolC. Our results suggest that ligand-mediated TolC-AcrA interface disruption represents a novel mechanism of efflux pump inhibition.

microbiology↗

bioRxiv2023

Repurposing Hsp90 inhibitors as antimicrobials targeting two-component systems identifies compounds leading to loss of bacterial membrane integrity

The discovery of antimicrobials with novel mechanisms of action is crucial to tackle the foreseen global health crisis due to antimicrobial resistance. Bacterial two-component signalling systems (TCS) are attractive targets for the discovery of novel antibacterial agents. TCS-encoding genes are found in all bacterial genomes and typically consist of a sensor histidine kinase (HK) and a response regulator (RR). Due to the conserved Bergerat fold in the ATP-binding domain of the TCS HK and the human chaperone Hsp90, there has been much interest in repurposing inhibitors of Hsp90 as antibacterial compounds. In this study, we explore the chemical space of the known Hsp90 inhibitor scaffold 3,4-diphenylpyrazole (DPP), building on previous literature to further understand their potential for HK inhibition. Six DPP analogues inhibited HK autophosphorylation in vitro and had good antimicrobial activity against Gram-positive bacteria. However, mechanistic studies showed that their antimicrobial activity was related to damage of bacterial membranes. In addition, DPP analogues were cytotoxic to mammalian cancer cell lines and induced the cell arrest phenotype shown for other Hsp90 inhibitors. We conclude that these DPP structures can be further optimized as specific disruptors of bacterial membranes providing binding to Hsp90 and cytotoxicity are lowered. With respect to the original hypothesis, the X-ray crystal structure of resorcinol, a substructure of the DPP derivatives, bound to the HK CheA represents a promising starting point for the fragment-based design of novel HK inhibitors.

microbiology↗