RESUMO
Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance.
Assuntos
Peptídeos Catiônicos Antimicrobianos/antagonistas & inibidores , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos/química , Peptídeos/farmacologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Catelicidinas/antagonistas & inibidores , Catelicidinas/química , Catelicidinas/metabolismo , Cecropinas/antagonistas & inibidores , Cecropinas/química , Cecropinas/metabolismo , Dicroísmo Circular , Relação Dose-Resposta a Droga , Hemólise/efeitos dos fármacos , Humanos , Magaininas/antagonistas & inibidores , Magaininas/química , Magaininas/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Dinâmica Molecular , Peptídeos/metabolismo , Ligação Proteica , Dobramento de Proteína , Multimerização Proteica , Estrutura Secundária de Proteína , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Biocompatible surfaces hold key to a variety of biomedical problems that are directly related to the competition between host-tissue cell integration and bacterial colonisation. A saving solution to this is seen in the ability of cells to uniquely respond to physical cues on such surfaces thus prompting the search for cell-instructive nanoscale patterns. Here we introduce a generic rationale engineered into biocompatible, titanium, substrates to differentiate cell responses. The rationale is inspired by cicada wing surfaces that display bactericidal nanopillar patterns. The surfaces engineered in this study are titania (TiO2) nanowire arrays that are selectively bactericidal against motile bacteria, while capable of guiding mammalian cell proliferation according to the type of the array. The concept holds promise for clinically relevant materials capable of differential physico-mechanical responses to cellular adhesion.