Abstract:Polymyxins are used as last-resort antibiotics, where other treatments have been ineffectual due to antibiotic resistance. However, resistance to polymyxins has also been now reported, therefore it is instructive to characterise at the molecular level, the mechanisms of action of polymyxins. Here we review insights into these mechanisms from molecular dynamics simulations and discuss the utility of simulations as a complementary technique to experimental methodologies.
“…9 Instead, the AMPs are adsorbed on the bacterial membrane and form hydrogen bonds with the lipid phosphate groups, disrupting the salt-bridges between phosphate groups and divalent cations, and destabilizing the close packing of the membrane. 1,33 The AMPs insertion in OM and IM correlates with the APL measurements (APL AMP.free -APL w.AMP ). This means a deeper AMP insertion lower (APL AMP.free -APL w.AMP ).…”
Section: Resultsmentioning
confidence: 92%
“…As a result, water translocation across bilayer occur, and the membrane becomes leaky resulting in membrane dysfunction. 33,34 On this basis, we studied the effect of the AMPs on water permeation in the OM and IM liposomes. The water density profiles are represented in Figure 9.…”
Section: Resultsmentioning
confidence: 99%
“…Moreover, some cationic AMPs are known to permeabilize the bacterial outer membrane via a competitive displacement of divalent cations. 33 The positively charged residues in the peptide bind the negatively charged LPS head groups leading to a divalent counterions displacement, along with structural changes in membrane integrity. 1 Therefore, the Ca 2+ displacement, together with the electrostatic repulsion between the cationic peptides and the Ca 2+ ions could decrease the Ca 2+ density in the liposomes inner cavity.…”
AntiMicrobial Resistance (AMR) is a worldwide health emergency. ESKAPE pathogens include the most relevant AMR bacterial families. In particular, Gram-negative bacteria stand out due to their cell envelope complexity which exhibits strong resistance to antimicrobials. A key element for AMR is the chemical structure of lipid A, modulating the physico-chemical properties of the membrane and permeability to antibiotics. Liposomes are used as models of bacterial membrane infective vesicles. In this work, coarse-grained molecular dynamics simulations were used to model liposomes from ESKAPE Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa). We captured the role of lipid A, cardiolipin and cholesterol on liposome morphology and physico-chemical properties. Additionally, the reported antimicrobial peptides Cecropin B1, JB95, and PTCDA1-kf, were used to unveil their implications on membrane disruption. This study opens promising avenues to understand the molecular keys of bacterial membranes and to develop new antimicrobials to overcome AMR.
“…9 Instead, the AMPs are adsorbed on the bacterial membrane and form hydrogen bonds with the lipid phosphate groups, disrupting the salt-bridges between phosphate groups and divalent cations, and destabilizing the close packing of the membrane. 1,33 The AMPs insertion in OM and IM correlates with the APL measurements (APL AMP.free -APL w.AMP ). This means a deeper AMP insertion lower (APL AMP.free -APL w.AMP ).…”
Section: Resultsmentioning
confidence: 92%
“…As a result, water translocation across bilayer occur, and the membrane becomes leaky resulting in membrane dysfunction. 33,34 On this basis, we studied the effect of the AMPs on water permeation in the OM and IM liposomes. The water density profiles are represented in Figure 9.…”
Section: Resultsmentioning
confidence: 99%
“…Moreover, some cationic AMPs are known to permeabilize the bacterial outer membrane via a competitive displacement of divalent cations. 33 The positively charged residues in the peptide bind the negatively charged LPS head groups leading to a divalent counterions displacement, along with structural changes in membrane integrity. 1 Therefore, the Ca 2+ displacement, together with the electrostatic repulsion between the cationic peptides and the Ca 2+ ions could decrease the Ca 2+ density in the liposomes inner cavity.…”
AntiMicrobial Resistance (AMR) is a worldwide health emergency. ESKAPE pathogens include the most relevant AMR bacterial families. In particular, Gram-negative bacteria stand out due to their cell envelope complexity which exhibits strong resistance to antimicrobials. A key element for AMR is the chemical structure of lipid A, modulating the physico-chemical properties of the membrane and permeability to antibiotics. Liposomes are used as models of bacterial membrane infective vesicles. In this work, coarse-grained molecular dynamics simulations were used to model liposomes from ESKAPE Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa). We captured the role of lipid A, cardiolipin and cholesterol on liposome morphology and physico-chemical properties. Additionally, the reported antimicrobial peptides Cecropin B1, JB95, and PTCDA1-kf, were used to unveil their implications on membrane disruption. This study opens promising avenues to understand the molecular keys of bacterial membranes and to develop new antimicrobials to overcome AMR.
“…Remarkably, for some specific AMPs, no membrane insertion has been observed experimentally, despite clear experimental evidence of membrane leakage and antibacterial activity 9 . Instead, the AMPs are adsorbed on the bacterial membrane and form hydrogen bonds with the lipid phosphate groups, disrupting the salt-bridges between phosphate groups and divalent cations, and destabilizing the close packing of the membrane 1 , 37 . Figure 7 AMP-Dependent APL.…”
“…The membrane disruption leads to the formation of a large number of cavities. As a result, water translocation across the bilayer takes place, and the membrane becomes leaky, resulting in membrane dysfunction 37 , 38 . Hence, we studied the effect of the AMPs on water permeation in the OM and IM liposomes.…”
AntiMicrobial Resistance (AMR) is a worldwide health emergency. ESKAPE pathogens include the most relevant AMR bacterial families. In particular, Gram-negative bacteria stand out due to their cell envelope complexity which exhibits strong resistance to antimicrobials. A key element for AMR is the chemical structure of lipid A, modulating the physico-chemical properties of the membrane and permeability to antibiotics. Liposomes are used as models of bacterial membrane infective vesicles. In this work, coarse-grained molecular dynamics simulations were used to model liposomes from ESKAPE Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa). We captured the role of lipid A, cardiolipin and cholesterol on liposome morphology and physico-chemical properties. Additionally, the reported antimicrobial peptides Cecropin B1, JB95, and PTCDA1-kf, were used to unveil their implications on membrane disruption. This study opens a promising starting point to understand molecular keys of bacterial membranes and to promote the discovery of new antimicrobials to overcome AMR.
Diderm bacteria employ β‐barrel outer membrane proteins (OMPs) as their first line of communication with their environment. These OMPs are assembled efficiently in the asymmetric outer membrane by the β‐Barrel Assembly Machinery (BAM). The multi‐subunit BAM complex comprises the transmembrane OMP BamA as its functional subunit, with associated lipoproteins (e.g., BamB/C/D/E/F, RmpM) varying across phyla and performing different regulatory roles. The ability of BAM complex to recognize and fold OM β‐barrels of diverse sizes, and reproducibly execute their membrane insertion, is independent of electrochemical energy. Recent atomic structures, which captured BAM–substrate complexes, show the assembly function of BamA can be tailored, with different substrate types exhibiting different folding mechanisms. Here, we highlight common and unique features of its interactome. We discuss how this conserved protein complex has evolved the ability to effectively achieve the directed assembly of diverse OMPs of wide‐ranging sizes (8–36 β‐stranded monomers). Additionally, we discuss how darobactin—the first natural membrane protein inhibitor of Gram‐negative bacteria identified in over five decades—selectively targets and specifically inhibits BamA. We conclude by deliberating how a detailed deduction of BAM complex—associated regulation of OMP biogenesis and OM remodeling will open avenues for the identification and development of effective next‐generation therapeutics against Gram‐negative pathogens.
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