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Preclinical Development of Pentamidine Analogs Identifies a Potent and Nontoxic Antibiotic Adjuvant
Craig R MacNair1,2, Maya A Farha1,2, Michael H Serrano-Wu3
1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
Abstract:
The difficulty in treating Gram-negative bacteria can largely be attributed to their highly impermeable outer membrane (OM), which serves as a barrier to many otherwise active antibiotics. This can be overcome with the use of perturbant molecules, which disrupt OM integrity and sensitize Gram-negative bacteria to many clinically available Gram-positive-active antibiotics. Although many new perturbants have been identified in recent years, most of these molecules are impeded by toxicity due to the similarities between pathogen and host cell membranes. For example, our group recently reported the cryptic OM-perturbing activity of the antiprotozoal drug pentamidine. Its development as an antibiotic adjuvant is limited, however, by toxicity concerns. Herein, we took a medicinal chemistry approach to develop novel analogs of pentamidine, aiming to improve its OM activity while reducing its off-target toxicity. We identified the compound P35, which induces OM disruption and potentiates Gram-positive-active antibiotics in Acinetobacter baumannii and Klebsiella pneumoniae. Relative to pentamidine, P35 has reduced mammalian cell cytotoxicity and hERG trafficking inhibition. Additionally, P35 outperforms pentamidine in a murine model of A. baumannii bacteremia. Together, this preclinical analysis supports P35 as a promising lead for further development as an OM perturbant.
Insights
Researchers developed P35, a novel pentamidine analog, to overcome antibiotic resistance in Gram-negative bacteria. P35 disrupts the outer membrane, enhancing antibiotic effectiveness while showing reduced toxicity compared to pentamidine.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Antimicrobial Resistance
Background:
- Gram-negative bacteria possess a challenging outer membrane (OM) barrier, limiting antibiotic efficacy.
- Perturbant molecules can disrupt OM integrity, sensitizing bacteria to antibiotics, but often exhibit host cell toxicity.
- Pentamidine shows OM-perturbing activity but is limited by toxicity concerns.
Purpose of the Study:
- To develop novel pentamidine analogs with improved OM-perturbing activity and reduced toxicity.
- To identify a lead compound for use as an antibiotic adjuvant against Gram-negative pathogens.
Main Methods:
- Medicinal chemistry approach to synthesize pentamidine analogs.
- Evaluation of OM disruption and antibiotic potentiation in *Acinetobacter baumannii* and *Klebsiella pneumoniae*.
- Assessment of mammalian cell cytotoxicity and hERG trafficking inhibition.
- In vivo efficacy testing in a murine model of *A. baumannii* bacteremia.
Main Results:
- Identified compound P35, which effectively disrupts the OM and potentiates Gram-positive-active antibiotics.
- P35 demonstrated reduced cytotoxicity and hERG trafficking inhibition compared to pentamidine.
- P35 showed superior performance in a murine model of *A. baumannii* bacteremia.
Conclusions:
- P35 is a promising lead compound for development as an OM perturbant.
- This novel analog offers a potential strategy to combat infections caused by Gram-negative bacteria.
- P35 represents an advancement in developing safer and more effective antibiotic adjuvants.
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