The importance of cyclic structure for Labaditin on its antimicrobial activity against Staphylococcus aureus.
Antimicrobial resistance has reached alarming levels in many countries, thus leading to a search for new classes of antibiotics, such as antimicrobial peptides whose activity is exerted by interacting specifically with the microorganism membrane. In this study, we investigate the molecular-level mechanism of action for Labaditin (Lo), a 10-amino acid residue cyclic peptide from Jatropha multifida with known bactericidal activity against Streptococcus mutans. We show that Lo is also effective against Staphylococcus aureus (S. aureus) but this does not apply to its linear analogue (L1). Using polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS), we observed with that the secondary structure of Lo was preserved upon interacting with Langmuir monolayers from a phospholipid mixture mimicking S. aureus membrane, in contrast to L1. This structure preservation for the rigid, cyclic Lo is key for the self-assembly of peptide nanotubes that induce pore formation in large unilamellar vesicles (LUVs), according to permeability assays and dynamic light scattering measurements. In summary, the comparison between Labaditin (Lo) and its linear analogue L1allowed us to infer that the bactericidal activity of Lo is more related to its interaction with the membrane. It does not require specific metabolic targets, which makes cyclic peptides promising for antibiotics without bacteria resistance.
Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil. Electronic address: simonebarbsa@gmail.com.
Simone C
SC
Barbosa
Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil.
Thatyane M
TM
Nobre
Department of Natural Sciences, Mid Sweden University, SE-851 70 Sundsvall, Sweden.
Diogo
D
Volpati
Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Pietro
P
Ciancaglini
Instituto de Química, Universidade Estadual Paulista, Araraquara, SP, Brazil.
Eduardo M
EM
Cilli
Departamento de Bioquímica e Biologia Molecular, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Brazil.
Esteban N
EN
Lorenzón
Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil.
Osvaldo N
ON
Oliveira
D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D031286:Jatropha / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010940:Plant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013055:Spectrophotometry, Infrared / Q000379:methods; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism
D000890:Anti-Infective Agents; D010456:Peptides, Cyclic; D010940:Plant Proteins; D053835:Unilamellar Liposomes; C000614923:labaditin
Antimicrobial peptide; Cyclic peptides; Labaditin; Langmuir monolayers; Large unilamellar vesicles; PM-IRRAS; Peptide nanotubes; Staphylococcus aureus