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PMB1 (cyan, white, blue, red) interaction with a bilayer containing lipid A (green) in both leaflets. Initially the PMB1 molecules are in the water layers in either side of the bilayer. A single
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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 molecu...
Citations
... Further insights into the polymyxin-LPS interaction have also come from several molecular dynamics (MD) simulation studies, which predict the behavior of a system when it is perturbed by some agents (Weerakoon et al., 2021). Using coarse-grained atomistic models of the bacterial OM the MD simulation studies have greatly complemented the data generated from biophysical experiments highlighting the importance of such approaches to understanding the molecular details of the polymyxin-LPS interactions (Jiang et al., 2021a;Weerakoon et al., 2021;Fu et al., 2022;Sun et al., 2022). ...
... Further insights into the polymyxin-LPS interaction have also come from several molecular dynamics (MD) simulation studies, which predict the behavior of a system when it is perturbed by some agents (Weerakoon et al., 2021). Using coarse-grained atomistic models of the bacterial OM the MD simulation studies have greatly complemented the data generated from biophysical experiments highlighting the importance of such approaches to understanding the molecular details of the polymyxin-LPS interactions (Jiang et al., 2021a;Weerakoon et al., 2021;Fu et al., 2022;Sun et al., 2022). Based on the MD simulation studies Fu et al., (2022) have proposed a model named SST for lipid Scramble, membrane phase Separation, and peptide Translocation, to provide insight into the polymyxin-OM interactions. ...
With the rising incidences of antimicrobial resistance (AMR) and the diminishing options of novel antimicrobial agents, it is paramount to decipher the molecular mechanisms of action and the emergence of resistance to the existing drugs. Polymyxin, a cationic antimicrobial lipopeptide, is used to treat infections by Gram-negative bacterial pathogens as a last option. Though polymyxins were identified almost seventy years back, their use has been restricted owing to toxicity issues in humans. However, their clinical use has been increasing in recent times resulting in the rise of polymyxin resistance. Moreover, the detection of "mobile colistin resistance (mcr)" genes in the environment and their spread across the globe have complicated the scenario. The mechanism of polymyxin action and the development of resistance is not thoroughly understood. Specifically, the polymyxin-bacterial lipopolysaccharide (LPS) interaction is a challenging area of investigation. The use of advanced biophysical techniques and improvement in molecular dynamics simulation approaches have furthered our understanding of this interaction, which will help develop polymyxin analogs with better bactericidal effects and lesser toxicity in the future. In this review, we have delved deeper into the mechanisms of polymyxin-LPS interactions, highlighting several models proposed, and the mechanisms of polymyxin resistance development in some of the most critical Gram-negative pathogens.
... For instance, earlier studies demonstrating the inhibitory effect on E. coli LolCDE 12 have shown significant promise in developing new anti-microbials 13 . Furthermore, LolA (of E. coli) has been proposed to function as a transporter of the antibiotic polymyxin 14 and it has also been debated whether or not LolA binds the inhibitory compound A22 15 . Crystal structures of LolA have previously been solved from mainly γ-proteobacteria such as Pseudomonas aeruginosa, E. coli and Yersinia pestis 16,17 . ...
... As a result, the OM is disrupted, and after passing through the periplasm, the IM can also be damaged 30 . In order to uncover the mechanism of polymyxin B transport from the OM to the IM, a molecular dynamics simulations study suggested that LolA and LolB are responsible for binding and transporting the molecule 14 . The idea was derived from the observation that polymyxin has a lipid tail that could theoretically bind LolA and LolB like the acyl chains of lipoproteins. ...
In Gram-negative bacteria, N-terminal lipidation is a signal for protein trafficking from the inner membrane (IM) to the outer membrane (OM). The IM complex LolCDE extracts lipoproteins from the membrane and moves them to the chaperone LolA. The LolA-lipoprotein complex crosses the periplasm after which the lipoprotein is anchored to the OM. In γ-proteobacteria anchoring is assisted by the receptor LolB, while a corresponding protein has not been identified in other phyla. In light of the low sequence similarity between Lol-systems from different phyla and that they may use different Lol components, it is crucial to compare representative proteins from several species. Here we present a structure–function study of LolA and LolB from two phyla: LolA from Porphyromonas gingivalis (phylum bacteroidota), and LolA and LolB from Vibrio cholerae (phylum proteobacteria). Despite large sequence differences, the LolA structures are very similar, hence structure and function have been conserved throughout evolution. However, an Arg-Pro motif crucial for function in γ-proteobacteria has no counterpart in bacteroidota. We also show that LolA from both phyla bind the antibiotic polymyxin B whereas LolB does not. Collectively, these studies will facilitate the development of antibiotics as they provide awareness of both differences and similarities across phyla.
... For instance, earlier studies demonstrating the inhibitory effect on E. coli LolCDE [12] have shown signi cant promise in developing new anti-microbials [13]. Furhermore, LolA (of E. coli) has been proposed to function as a transporter of the antibiotic polymyxin [14] and it has also been debated whether or not LolA binds the inhibitory compound A22 [15]. Crystal structures of LolA have previously been solved from mainly γproteobacteria such as Pseudomonas aeruginosa, E. coli and Yersinia pestis [16,17]. ...
... As a result, the OM is disrupted, and after passing through the periplasm, the IM can also be damaged. In order to uncover the mechanism of polymyxin B transport from the OM to the IM, a molecular dynamics simulations study suggested that LolA and LolB are responsible for binding and transporting the molecule [14]. The idea was derived from the observation that polymyxin has a lipid tail that could theoretically bind LolA and LolB like the acyl chains of lipoproteins. ...
In Gram-negative bacteria, N-terminal lipidation is a signal for protein trafficking from the inner membrane (IM) to the outer membrane (OM). The IM complex LolCDE extracts lipoproteins from the membrane and moves them to the chaperone LolA. The LolA-lipoprotein complex crosses the periplasm after which the lipoprotein is anchored to the OM. In g-proteobacteria anchoring is assisted by the receptor LolB, while a corresponding protein has not been identified in other phyla. In light of the low sequence similarity between Lol-systems from different phyla and that they may use different Lol components, it is crucial to compare representative proteins from several species.
Here we present a structure-function study of LolA and LolB from two phyla: LolA from Porphyromonas gingivalis(phylum bacteroidota), and LolA and LolB from Vibiro cholerae (phylum proteobacteria). Despite large sequence differences, the LolA structures are very similar, hence structure and function have been conserved throughout evolution. However, an Arg-Pro motif crucial for function in g-proteobacteria has no counterpart in bacteriodota. We also show that LolA from both phyla bind the antibiotic polymyxin B whereas LolB does not. Collectively, these studies will facilitate the development of antibiotics as they provide awareness of both differences and similarities across phyla.
... 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.
... Cationic AMPs eventually displace divalent cations because they have at least three orders of magnitude higher affinities for LPS and are much larger, disrupting the outer membrane locally. However, the detailed explanation of this process is still unknown [73]. ...
... As reported in the literature, LPS has very slow dynamics; therefore, no significant insertion is expected to be observed during simulations on the order of nanoseconds [73]. Accordingly, simulations captured only the initial contact of adepantin-1 with the outer membrane but also indicated the differences in peptides interactions with the O-antigen and core region of the outer membrane. ...
Antimicrobial peptides (AMPs) can be directed to specific membranes based on differences in lipid composition. In this study, we performed atomistic and coarse-grained simulations of different numbers of the designed AMP adepantin-1 with a eukaryotic membrane, cytoplasmic Gram-positive and Gram-negative membranes, and an outer Gram-negative membrane. At the core of adepantin-1’s behavior is its amphipathic α-helical structure, which was implemented in its design. The amphipathic structure promotes rapid self-association of peptide in water or upon binding to bacterial membranes. Aggregates initially make contact with the membrane via positively charged residues, but with insertion, the hydrophobic residues are exposed to the membrane’s hydrophobic core. This adaptation alters the aggregate’s stability, causing the peptides to diffuse in the polar region of the membrane, mostly remaining as a single peptide or pairing up to form an antiparallel dimer. Thus, the aggregate’s proposed role is to aid in positioning the peptide into a favorable conformation for insertion. Simulations revealed the molecular basics of adepantin-1 binding to various membranes, and highlighted peptide aggregation as an important factor. These findings contribute to the development of novel anti-infective agents to combat the rapidly growing problem of bacterial resistance to antibiotics.
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.
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.
The current issue (volume 13 issue 62,021) is a Special Issue jointly dedicated to scientific content presented at the 20th triennial IUPAB Congress that was held in conjunction with both the 45th Annual Meeting of the Brazilian Biophysical Society (Sociedade Brasileira de Biofísica - SBBf) and the 50th Annual Meeting of the Brazilian Society for Biochemistry and Molecular Biology (Sociedade Brasileira de Bioquímica e Biologia Molecular – SBBq). In addition to describing the scientific and nonscientific content arising from the meeting this sub-editorial also provides a look back at some of the high points for Biophysical Reviews in the year 2021 before going on to describe a number of matters of interest to readers of the journal in relation to the coming year of 2022.
