title: Synthesis, stability and mechanistic studies of potent anticryptococcal hexapeptides.
abstract: The growing incidents of cryptococcosis in immuno-compromised patients have created a need for novel drug therapies capable of eradicating the disease. The peptide-based drug therapy offers many advantages over the traditional therapeutic agents, which has been exploited in the present study by synthesizing a series of hexapeptides that exhibits promising activity against a panel of Gram-negative and Gram-positive bacteria and various pathogenic fungal strains; the most exemplary activity was observed against Cryptococcus neoformans. The peptides 3, 24, 32 and 36 displayed potent anticryptococcal activity (IC50= 0.4-0.46 μg/mL, MIC = 0.63-1.25 μg/mL, MFC = 0.63-1.25 μg/mL), and stability under proteolytic conditions. Besides this, several other peptides displayed promising inhibition of pathogenic bacteria. The prominent ones include peptides 18-20, and 26 that exhibited IC50values ranged between 2.1 and 3.6 μg/mL, MICs of 5-20 μg/mL and MBCs of 10-20 μg/mL against Staphylococcus aureus and methicillin-resistant S. aureus. The detailed mechanistic study on selected peptides demonstrated absolute selectivity towards the bacterial membranes and fungal cells by causing perturbations in the cell membranes, confirmed by the scanning electron microscopy and transmission electron microscopy studies.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab, 160 062, India.
authors.forename: Kitika
authors.initials: K
authors.lastname: Shenmar
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab, 160 062, India.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Sharma
authors.affiliation: Department of Applied Sciences, University Institute of Engineering and Technology (U.I.E.T.), Panjab University, Sector-25, Chandigarh, 160014, India.
authors.forename: Nishima
authors.initials: N
authors.lastname: Wangoo
authors.affiliation: Department of Microbial Biotechnology, Panjab University, Sector-14, Chandigarh, 160014, India.
authors.forename: Indresh K
authors.initials: IK
authors.lastname: Maurya
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab, 160 062, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
authors.forename: Shabana I
authors.initials: SI
authors.lastname: Khan
authors.affiliation: National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Jacob
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab, 160 062, India.
authors.forename: Kulbhushan
authors.initials: K
authors.lastname: Tikoo
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab, 160 062, India. Electronic address: rahuljain@niper.ac.in.
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000187:drug effects; D004355:Drug Stability; D020128:Inhibitory Concentration 50; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D010455:Peptides
keywords: Amphiphilic hexapeptides; Anticryptococcal; Electron microscopy; Proteolysis; Solid phase peptide synthesis