Key Takeaways & Executive Findings
- •• • LaP-Col achieved a maximum tolerated dose (MTD) >20-fold higher than colistin and minimal nephrotoxicity, directly addressing the dose-limiting toxicity that restricts colistin to last-resort status and enabling safer intravenous administration. • • In a murine P. aeruginosa pneumonia model, intravenous LaP-Col accumulated in infected lungs and significantly reduced lung injury scores compared to infected controls (p < 0.05), demonstrating infection-site targeting and therapeutic efficacy. • • The ROS-responsive phenylboronic acid linker enables selective activation at infection sites where elevated ROS levels cleave the linker, releasing active colistin; this contrasts with the slow, non-selective hydrolysis of colistin methanesulfonate, which compromises antibacterial efficacy. • • The lactosyl moiety confers bacterial targeting, likely via lectin-like interactions, enhancing drug accumulation at infection foci and improving survival rates in vivo, as evidenced by improved mouse survival in the pneumonia model.
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Abstract
The clinical utility of colistin, a last-resort antibiotic against multidrug-resistant Gram-negative pathogens, is severely constrained by dose-limiting nephrotoxicity (up to 60% incidence) and poor infection-site targeting. Existing prodrug approaches, such as colistin methanesulfonate, rely on slow, non-selective hydrolysis that reduces systemic toxicity but also diminishes antibacterial efficacy at the infection foci. Here we report a conjugate strategy that combines infection-activatable release with bacterial targeting. A series of colistin prodrugs were synthesized by attaching a reactive oxygen species (ROS)-responsive phenylboronic acid linker to all primary amines of colistin, followed by covalent conjugation to sugars via boronic acid–diol complexation. The lead candidate, lactosyl-functionalized colistin prodrug (LaP-Col), exhibited minimal toxicity toward normal tissues and actively targeted bacteria. LaP-Col displayed a maximum tolerated dose exceeding that of colistin by more than 20-fold and minimal nephrotoxicity. In a murine model of Pseudomonas aeruginosa pneumonia, intravenous LaP-Col accumulated in infected lungs, effectively killed bacteria, and significantly improved therapeutic efficacy and survival rates. This prodrug architecture offers a generalizable route to mitigate the inherent toxicity of potent antimicrobial peptides while enhancing site-specific targeting.
1. Introduction
Colistin remains the last-line therapeutic option for life-threatening infections caused by multidrug-resistant Gram-negative bacteria, yet its clinical deployment is severely hampered by substantial nephrotoxicity, affecting up to 60% of treated patients. This toxicity narrows the therapeutic window and limits the maximum safe intravenous dose, while inefficient targeting following systemic administration often results in subtherapeutic concentrations at infection sites. The current standard prodrug, colistin methanesulfonate, mitigates toxicity through slow, non-selective hydrolysis of methanesulfonate groups, but this unselective activation also reduces the effective concentration of colistin at the infection foci, undermining antibacterial efficacy.
To overcome this trade-off, we designed a lactosyl-functionalized, ROS-responsive colistin prodrug (LaP-Col) that couples infection-specific activation with bacterial targeting. The phenylboronic acid linker is cleaved by elevated ROS at infection sites, releasing active colistin selectively, while the lactosyl moiety directs the prodrug to bacteria. This dual mechanism aims to reduce systemic toxicity and enhance drug accumulation at the infection foci, as validated in a murine pneumonia model. The strategy offers a generalizable platform for modifying other potent but toxic antimicrobial peptides.
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ZHANG Yuhao, DENG Yingxue, SU Chanjuan, WU Kangxiu, LI Chengrun, WANG Juntao, ZHANG Houbing, LUO Dong, HUANG Songyin, ZHAO Liping, XIONG Menghua, BAO Yan (2025). A conjugate strategy capable of targeting bacteria and selectively being activated at infection sites. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3360-x
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Frequently Asked Questions
What is the maximum tolerated dose (MTD) of LaP-Col compared to colistin, and how does this translate to clinical safety?
LaP-Col exhibits an MTD over 20 times greater than that of colistin in preclinical models, with minimal nephrotoxicity. This >20-fold improvement in MTD directly addresses the dose-limiting nephrotoxicity of colistin, potentially enabling higher intravenous doses and a broader therapeutic window in clinical settings.
How does the ROS-responsive phenylboronic acid linker ensure selective activation at infection sites, and what is the release mechanism?
The phenylboronic acid linker is cleaved by elevated reactive oxygen species (ROS) present at infection sites, triggering the release of active colistin. This selective activation contrasts with the slow, non-selective hydrolysis of colistin methanesulfonate, thereby reducing systemic toxicity while maintaining high antibacterial concentrations at the infection foci.
What evidence supports bacterial targeting by the lactosyl moiety, and how does it improve therapeutic efficacy?
In a murine P. aeruginosa pneumonia model, intravenous LaP-Col accumulated in infected lungs and significantly reduced lung injury scores compared to infected controls (p < 0.05). The lactosyl moiety likely mediates binding to bacterial lectins, enhancing drug accumulation at infection sites and improving survival rates.
What are the scalability and cost considerations for synthesizing LaP-Col compared to colistin methanesulfonate?
The synthesis involves attaching a phenylboronic acid linker to all amines of colistin followed by conjugation to lactose. While this multi-step process may increase manufacturing complexity, the well-defined structure and use of readily available reagents (phenylboronic acid, lactose) suggest feasible scale-up. Cost parity with colistin methanesulfonate will depend on optimization of reaction yields and purification steps.
Does LaP-Col retain antibacterial activity against colistin-resistant strains, and what is the resistance propensity?
The study validated efficacy against P. aeruginosa in a pneumonia model, but data on colistin-resistant strains are not provided. The ROS-responsive release mechanism may not overcome colistin-specific resistance mechanisms (e.g., mcr-1). Further studies are needed to assess cross-resistance and resistance development potential.
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