Selectivity Modulation of Small Cationic Membrane-Active Cyclic Peptides with Broad-Spectrum Activity against Bacteria and Fungi

Authors

Sandeep Lohan, Chapman UniversityFollow
Rakesh Kumar Tiwari, Chapman UniversityFollow
Innokentiy Maslennikov, Chapman UniversityFollow
Kaustav Das Gupta, The Lundquist Institute for Biomedical Innovation at Harbor-University of California
Shakti Singh, The Lundquist Institute for Biomedical Innovation at Harbor-University of California
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

2-27-2026

Abstract

To investigate how ring size and backbone flexibility influence antimicrobial potency and cytotoxicity, we synthesized a series of macrocyclic peptides of lead peptide p1 (c[Arg-Arg-arg-arg-dip-Trp-dip]) by incorporating Gly, 2-aminoethoxyacetic acid (EAA), or 2,4-diaminobutyric acid (Dab). Two optimized peptides, 6b and 10b, retained broad-spectrum activity against drug-resistant Gram-positive (MIC, 1.5–6.2 μg/mL) and Gram-negative bacteria (MIC, 4–25 μg/mL), as well as pathogenic fungi, while exhibiting enhanced selectivity for microbial cells. Their therapeutic indices (TI ∼407 and ∼394, respectively) were ∼2-fold higher than p1, indicating improved safety. Both peptides remained effective against Gram-negative pathogens beyond the reach of daptomycin, were rapidly bactericidal, and eradicated bacterial and fungal biofilms. Mechanistic studies (e.g., calcein-leakage and extracellular ATP leakage assays) confirmed a membranolytic mode of action. NMR analysis revealed a distinct “sandwich” conformation in 6b that rationalizes its improved selectivity. Both peptides exhibited high plasma stability (t1/2 ∼ 6–8 h), supporting their therapeutic potential.

Comments

This article was originally published in Journal of Medicinal Chemistry, volume number, issue number, in 2026. https://doi.org/10.1021/acs.jmedchem.5c03707

Recommended Citation

Lohan, S.; Tiwari, R. K.; Maslennikov, I.; Gupta, K. D.; Singh, S.; Parang, K. Selectivity modulation of small cationic membrane-active cyclic peptides with broad-spectrum activity against bacteria and fungi. J. Med. Chem. https://doi.org/10.1021/acs.jmedchem.5c03707

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The authors

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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.