title: Enhanced Cationic Charge is a Key Factor in Promoting Staphylocidal Activity of α-Melanocyte Stimulating Hormone via Selective Lipid Affinity.
abstract: The steady rise in antimicrobial resistance poses a severe threat to global public health by hindering treatment of an escalating spectrum of infections. We have previously established the potent activity of α-MSH, a 13 residue antimicrobial peptide, against the opportunistic pathogen Staphylococcus aureus. Here, we sought to determine whether an increase in cationic charge in α-MSH could contribute towards improving its staphylocidal potential by increasing its interaction with anionic bacterial membranes. For this we designed novel α-MSH analogues by replacing polar uncharged residues with lysine and alanine. Similar to α-MSH, the designed peptides preserved turn/random coil conformation in artificial bacterial mimic 1,2-dimyristoyl-sn-glycero-3-phosphocholine:1,2-dimyristoyl-sn-glycero-3-phospho-rac-(1-glycerol) (7:3, w/w) vesicles and showed preferential insertion in the hydrophobic core of anionic membranes. Increased cationic charge resulted in considerable augmentation of antibacterial potency against MSSA and MRSA. With ~18-fold better binding than α-MSH to bacterial mimic vesicles, the most charged peptide KKK-MSH showed enhanced membrane permeabilization and depolarization activity against intact S. aureus. Scanning electron microscopy confirmed a membrane disruptive mode of action for KKK-MSH. Overall, increasing the cationic charge improved the staphylocidal activity of α-MSH without compromising its cell selectivity. The present study would help in designing more effective α-MSH-based peptides to combat clinically relevant staphylococcal infections.
authors.affiliation: Antimicrobial Research Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Singh
authors.affiliation: Antimicrobial Research Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors.forename: Seema
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Antimicrobial Research Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors.forename: Sana
authors.initials: S
authors.lastname: Mumtaz
authors.affiliation: Biochemistry and Environmental Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors.forename: Nancy
authors.initials: N
authors.lastname: Maurya
authors.affiliation: Biochemistry and Environmental Toxicology Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors.forename: Ilora
authors.initials: I
authors.lastname: Ghosh
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi-110020, India.
authors.forename: Shivangi
authors.initials: S
authors.lastname: Khanna
authors.affiliation: CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi-110020, India.
authors.forename: Vivek T
authors.initials: VT
authors.lastname: Natarajan
authors.affiliation: Antimicrobial Research Laboratory, School of Environmental Sciences, Jawaharlal Nehru University, New Delhi-110067, India.
authors.forename: Kasturi
authors.initials: K
authors.lastname: Mukhopadhyay
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002412:Cations / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D050356:Lipid Metabolism; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008855:Microscopy, Electron, Scanning; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000521:alpha-MSH / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D002412:Cations; D000521:alpha-MSH