Rational design of ivacaftor-derived antimicrobial peptidomimetics: Membrane-targeting strategy enhances
Rongcui Zhong1, Lingqing Xu1, Jiaxuan Wu1
1Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, State Key Laboratory of Respiratory Disease, Affiliated Qingyuan Hospital, and School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Abstract:
Antibiotic resistance poses an escalating global public health threat, underscoring the urgent need for novel antimicrobials to combat multidrug-resistant (MDR) pathogens. This study employed an antimicrobial peptide-mimicking strategy to design and synthesize a series of ivacaftor-based derivatives. The candidate compound 27 was identified because of its remarkable broad-spectrum antibacterial activity (MICs = 0.195-3.125 μg/mL), low hemolytic toxicity (HC50 > 200 μg/mL), high cellular safety (CC50 > 50 μg/mL), and good stability in saline and plasma. Further biological exploration revealed that 27 exerted its rapid bactericidal effects by damaging bacterial cell membranes, resulting in a very low frequency of drug resistance. More crucially, in vivo toxicity studies and murine corneal infection models with Staphylococcus aureus confirmed the low toxicity and potent antibacterial efficacy of 27. In summary, as a novel molecular entity, compound 27 is a valuable broad-spectrum, low-toxicity candidate antibacterial agent capable of combating multidrug-resistant (MDR) bacteria.
Insights
A novel ivacaftor-based compound, 27, shows broad-spectrum antibacterial activity against multidrug-resistant pathogens. It demonstrates low toxicity and potent efficacy in preclinical models, offering a promising new candidate for combating resistant infections.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Pharmacology
Background:
- Antibiotic resistance is a critical global health challenge requiring new antimicrobial agents.
- Multidrug-resistant (MDR) pathogens necessitate the development of novel therapeutic strategies.
- Antimicrobial peptides (AMPs) offer a source of inspiration for novel drug design.
Purpose of the Study:
- To design and synthesize novel ivacaftor-based derivatives with antimicrobial properties.
- To evaluate the antibacterial activity, toxicity, and stability of synthesized compounds.
- To investigate the mechanism of action and in vivo efficacy of promising candidates.
Main Methods:
- Synthesis of ivacaftor-based derivatives.
- Determination of minimum inhibitory concentrations (MICs) against various bacterial strains.
- Assessment of hemolytic and cellular toxicity (HC50, CC50).
- Evaluation of compound stability in physiological conditions.
- Bactericidal mechanism studies, including bacterial membrane damage assessment.
- In vivo efficacy testing in a murine corneal infection model.
Main Results:
- Compound 27 exhibited broad-spectrum antibacterial activity with low MIC values (0.195-3.125 μg/mL).
- Compound 27 demonstrated favorable safety profiles, with low hemolytic toxicity (HC50 > 200 μg/mL) and high cellular safety (CC50 > 50 μg/mL).
- The compound showed good stability in saline and plasma.
- Compound 27 rapidly killed bacteria by damaging cell membranes, leading to a low frequency of resistance development.
- In vivo studies confirmed the low toxicity and potent antibacterial efficacy of compound 27 against Staphylococcus aureus.
Conclusions:
- Compound 27 is a novel molecular entity with significant potential as an antibacterial agent.
- Its broad-spectrum activity, low toxicity, and favorable stability make it a promising candidate for combating MDR bacteria.
- Further development of compound 27 could address the urgent need for new treatments against antibiotic-resistant infections.
