Biology subjects

Akhir, A.

Publications and source records attributed to Akhir, A..

3 recordsLinked to original sources

bioRxiv2026

Lysosomal acid lipase regulates cholesterol metabolism during phagosomal maturation

Phagocytosis, a central process in innate immunity, depends on dynamic lipid remodelling, yet how cholesterol accumulates on late phagosomes remains unresolved. Here, we identify lysosomal acid lipase (LIPA) as a key cholesterol ester (CE) hydrolase driving cholesterol mobilization during phagosomal maturation. Using integrated lipidomics, chemoproteomics, and biochemical assays, we show that LIPA exhibits acidic CE hydrolase activity enriched on late phagosomes, generating free cholesterol essential for lipid raft formation. Pharmacologically inhibiting LIPA disrupts cholesterol-rich lipid raft assembly, impairs phagosomal trafficking, and alters pathogen fate - enhancing Staphylococcus aureus persistence, while restricting Mycobacterium tuberculosis survival. These findings reveal that LIPA couples cholesterol metabolism to phagocytosis, defining a mechanistic link between lipid catabolism and antimicrobial defence. By positioning CE hydrolysis as a critical determinant of phagosomal dynamics, our work uncovers a metabolic checkpoint in innate immunity and identifies LIPA as a potential therapeutic node in infection and inflammation.

biochemistry↗

bioRxiv2025

A Platinum Butterfly Effect: Small Changes Turn an Anticancer Drug into a Non-toxic Metalloantibiotic with In Vivo Efficacy

Widespread resistance to all clinically used antibiotics has sparked investigations into alternative sources for novel and effective antimicrobial agents. Metal-based compounds (metalloantibiotics) have emerged as a promising class of potential antibiotics exhibiting high hit rates against critical bacterial pathogens while not displaying higher toxicity than organic compounds. Here, we describe the exploration of a novel class of non-toxic, Gram-positive acting platinum-based antibacterial agents with micro to nanomolar activity against a range of methicillin and vancomycin-resistant Staphylococcus aureus strains. Structure-activity relationship (SAR) studies revealed that modifications of the core scaffold result in reduced antibacterial activity. Mode of action studies investigations showed that lead compound Pt1 did not impair cell division, RNA, protein, or cell wall synthesis, nor did it affect membrane integrity or potential. Instead, akin to the structurally similar anticancer drug cisplatin (CisPt), Pt1 treatment resulted in reduced DNA staining, visible nucleoid compaction, and activation of DNA damage repair responses. Importantly, we could show that Pt1 is able to interact with and damage DNA directly, resulting in DNA strand breaks and fragmentation. Pt1 activity can be reduced significantly by high amounts of a hydroxyl radical scavenger. Derivative Pt8, which retained DNA-damaging activity but was less potent in terms of antibacterial activity, was not affected by the presence of radical scavengers, suggesting that Pt1 possesses a multimodal mechanism. In line with this observation, no resistance development to Pt1 was observed over the course of 36 passages. Finally, we could demonstrate the in vivo activity of Pt1, which significantly reduced the bacterial load in a murine S. aureus skin infection model. Altogether, these findings shed light on the SAR and antibacterial mode of action of a novel class of platinum metalloantibiotics, validate its in vivo efficacy, and pave the way for further exploration of platinum compounds as novel drug candidates with a highly attractive activity profile.

microbiology↗

bioRxiv2023

Intracellular Accumulation-Driven Potentiation of Moxifloxacin Against non-replicating drug-tolerant Mycobacterium tuberculosis through a Prodrug

Most front-line tuberculosis drugs are ineffective against hypoxic non-replicating drug-tolerant Mycobacterium tuberculosis (Mtb) contributing to phenotypic antimicrobial resistance (AMR). This is largely due to the poor permeability in the thick and waxy cell wall of persister cells, leading to diminished drug accumulation and reduced drug-target engagement. Here, using an "arm-to-disarm" prodrug approach, we demonstrate that non-replicating Mtb persisters can be sensitized to Moxifloxacin (MXF), a front-line TB drug. We design and develop a series of nitroheteroaryl MXF prodrugs that are substrates for bacterial nitroreductases (NTR), a class of enzymes that are over-expressed in hypoxic Mtb. Enzymatic activation involves electron-transfer to the nitroheteroaryl compound followed by protonation via water that contributes to the rapid cleavage rate of the protective group by NTR to produce the active drug. Phenotypic and genotypic data are fully consistent with MXF-driven lethality of the prodrug in Mtb with the protective group being a relatively innocuous bystander. The prodrug increased intracellular concentrations of MXF than MXF alone and is more lethal than MXF in non-replicating persisters. Hence, arming drugs to improve permeability, accumulation and drug-target engagement is a new therapeutic paradigm to disarm phenotypic AMR.

microbiology↗