Antibacterial Mechanisms of Polymyxin and Bacterial Resistance

Yu, Zhiliang; Qin, Wangrong; Lin, Jianxun; Fang, Shisong; Qiu, Juanping

doi:10.1155/2015/679109

Cited by 189 publications

(201 citation statements)

References 83 publications

(116 reference statements)

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“…The antibiotic PMB permeabilizes the OM before targeting and disrupting the cytoplasmic membrane in E. coli (33,34). As a result, PMB causes release into the medium of not only periplasmic ␤-lactamase but also cytoplasmic ␤-galactosidase (35,36), as confirmed in our studies (Fig.…”

Section: Classsupporting

confidence: 85%

A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli

Urfer

Bogdanović

Monte

et al. 2016

Journal of Biological Chemistry

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Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel ␤-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The discovery of novel antibiotics with new mechanisms of action is an important goal in antibiotic research to combat infections caused by multidrug-resistant bacteria, in particular Gram-negative microorganisms with their unique asymmetric outer membrane (OM) 3 (1). Naturally occurring cationic host defense peptides that form part of the innate immunity in many organisms have recently attracted great interest in the search for new clinically useful antibiotics (2). We explore here an approach to antibiotic discovery based upon host defense peptide-inspired macrocyclic peptidomimetics as a potential source of antibiotics displaying target selectivity and potency not seen with naturally occurring host defense peptides. In previous work (3), we described a family of macrocyclic ␤-hairpin peptidomimetics with potent and selective antimicrobial activity against Pseudomonas spp., which were shown to have a novel mechanism of action targeting the ␤-barrel outer membrane protein LptD in Pseudomonas aeruginosa and inhibiting its key lipopolysaccharide (LPS) transport function in OM biogenesis (4). We report here the discovery of a new conformationally constrained ␤-hairpin peptidomimetic (called JB-95) having potent antimicrobial activity against a panel of Grampositive and Gram-negative bacteria and, in particular, against Escherichia coli. JB-95 shows minimal inhibitory concentrations (MICs) of ϳ0.25 g/ml against E. coli, including many multidrug-resistant clinical strains. We report the solution structure of JB-95 and investigations into its mechanism of action against E. coli. Experimental ProceduresPeptide Synthesis-The methods for synthesis and characterization of all peptides have been described previously (5). JB-95 was of Ͼ95% purity by analytical reverse phase HPLC ( Antibacterial Assays-MICs were determined in microtiter plates in Mueller-Hinton-I (MH-I) medium using the broth

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Section: Classsupporting

confidence: 85%

A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli

Urfer

Bogdanović

Monte

et al. 2016

Journal of Biological Chemistry

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“…We previously reported the complete genome of this strain [8], and we identified that it has a truncated mgrB gene, consistent with reports that mutations in this gene represent one of the various mechanisms for acquired colistin resistance [9–11]. Despite Kp13 being already resistant to polymyxin B, we aimed to induce additional adaptive responses by growth in high polymyxin B concentrations while also probing in vitro the effects of diverse environmental stimuli.…”

Section: Introductionsupporting

confidence: 73%

The polymyxin B-induced transcriptomic response of a clinical, multidrug-resistant Klebsiella pneumoniae involves multiple regulatory elements and intracellular targets

et al. 2016

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BackgroundThe emergence of multidrug-resistant Klebsiella pneumoniae is a major public health concern. Many K. pneumoniae infections can only be treated when resorting to last-line drugs such as polymyxin B (PB). However, resistance to this antibiotic is also observed, although insufficient information is described on its mode of action as well as the mechanisms used by resistant bacteria to evade its effects. We aimed to study PB resistance and the influence of abiotic stresses in a clinical K. pneumoniae strain using whole transcriptome profiling.ResultsWe sequenced 12 cDNA libraries of K. pneumoniae Kp13 bacteria, from two biological replicates of the original strain Kp13 (Kp13) and five derivative strains: induced high-level PB resistance in acidic pH (Kp13pH), magnesium deprivation (Kp13Mg), high concentrations of calcium (Kp13Ca) and iron (Kp13Fe), and a control condition with PB (Kp13PolB). Our results show the involvement of multiple regulatory loci that differentially respond to each condition as well as a shared gene expression response elicited by PB treatment, and indicate the participation of two-regulatory components such as ArcA-ArcB, which could be involved in re-routing the K. pneumoniae metabolism following PB treatment. Modules of co-expressed genes could be determined, which correlated to growth in acid stress and PB exposure. We hypothesize that polymyxin B induces metabolic shifts in K. pneumoniae that could relate to surviving against the action of this antibiotic.ConclusionsWe obtained whole transcriptome data for K. pneumoniae under different environmental conditions and PB treatment. Our results supports the notion that the K. pneumoniae response to PB exposure goes beyond damaged membrane reconstruction and involves recruitment of multiple gene modules and intracellular targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3070-y) contains supplementary material, which is available to authorized users.

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“…The tight packing of the hydrophobic acyl chains in lipid A plays a role in stabilizing the outer membrane. 26 The inner core of LPS is highly conserved among bacterial species 23 and typically consists of 3-deoxy- d -manno-octulosonic acid (Kdo) and heptose sugars (Figure 2). With the exception of Neisseria meningitides, 27 lipid A and at least one Kdo (from the inner LPS core) are required for cell viability in LPS-producing, Gram-negative bacteria.…”

Section: Components Of the Bacterial Cell Wall Contribute To Cell Mecmentioning

confidence: 99%

Bacterial Cell Mechanics

2017

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Cellular mechanical properties play an integral role in bacterial survival and adaptation. Historically, the bacterial cell wall and, in particular, the layer of polymeric material called the peptidoglycan were the elements to which cell mechanics could be primarily attributed. Disrupting the biochemical machinery that assembles the peptidoglycan (e.g., using the β-lactam family of antibiotics) alters the structure of this material, leads to mechanical defects, and results in cell lysis. Decades after the discovery of peptidoglycan-synthesizing enzymes, the mechanisms that underlie their positioning and regulation are still not entirely understood. In addition, recent evidence suggests a diverse group of other biochemical elements influence bacterial cell mechanics, may be regulated by new cellular mechanisms, and may be triggered in different environmental contexts to enable cell adaptation and survival. This review summarizes the contributions that different biomolecular components of the cell wall (e.g., lipopolysaccharides, wall and lipoteichoic acids, lipid bilayers, peptidoglycan, and proteins) make to Gram-negative and Gram-positive bacterial cell mechanics. We discuss the contribution of individual proteins and macromolecular complexes in cell mechanics and the tools that make it possible to quantitatively decipher the biochemical machinery that contributes to bacterial cell mechanics. Advances in this area may provide insight into new biology and influence the development of antibacterial chemotherapies.

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Antibacterial Mechanisms of Polymyxin and Bacterial Resistance

Cited by 189 publications

References 83 publications

A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli

A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli

The polymyxin B-induced transcriptomic response of a clinical, multidrug-resistant Klebsiella pneumoniae involves multiple regulatory elements and intracellular targets

Bacterial Cell Mechanics

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