scholarly journals Structural Basis for Kinase-Mediated Macrolide Antibiotic Resistance

Structure ◽  
2017 ◽  
Vol 25 (5) ◽  
pp. 750-761.e5 ◽  
Author(s):  
Desiree H. Fong ◽  
David L. Burk ◽  
Jonathan Blanchet ◽  
Amy Y. Yan ◽  
Albert M. Berghuis
Keyword(s):  
Antibiotic Resistance ◽  
Macrolide Antibiotic ◽  
Structural Basis

scholarly journals The evolution of substrate discrimination in macrolide antibiotic resistance enzymes

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Andrew C. Pawlowski ◽  
Peter J. Stogios ◽  
Kalinka Koteva ◽  
Tatiana Skarina ◽  
Elena Evdokimova ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Macrolide Antibiotic ◽  
Substrate Discrimination

Medicinal Au(i) compounds targeting urease as prospective antimicrobial agents: unveiling the structural basis for enzyme inhibition

2021 ◽  
Author(s):  
Luca Mazzei ◽  
Lara Massai ◽  
Michele Cianci ◽  
Luigi Messori ◽  
Stefano Ciurli
Keyword(s):  
Antibiotic Resistance ◽  
Enzyme Inhibition ◽  
Antimicrobial Agents ◽  
Antimicrobial Properties ◽  
New Drugs ◽  
Structural Basis ◽  
Great Promise ◽  
Gold Compounds

A few gold compounds were recently found to show antimicrobial properties in vitro, holding great promise for the discovery of new drugs to overcome antibiotic resistance.

scholarly journals Antibiotic Resistance inStreptococcus pneumoniaeafter Azithromycin Distribution for Trachoma

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Derek K-H. Ho ◽  
Christian Sawicki ◽  
Nicholas Grassly
Keyword(s):  
Antibiotic Resistance ◽  
Web Of Science ◽  
Macrolide Antibiotic ◽  
Control Strategies ◽  
Risk Of Bias ◽  
Community Settings ◽  
Inclusion Criteria ◽  
Potential Sources ◽  
Blinding Trachoma

Trachoma is caused byChlamydia trachomatisand is a leading cause of blindness worldwide. Mass distribution of azithromycin (AZM) is part of the strategy for the global elimination of blinding trachoma by 2020. Although resistance to AZM inC. trachomatishas not been reported, there have been concerns about resistance in other organisms when AZM is administered in community settings. We identified studies that measured pneumococcal prevalence and resistance to AZM following mass AZM provision reported up to 2013 in Medline and Web of Science databases. Potential sources of bias were assessed using the Cochrane Risk of Bias Tool. A total of 45 records were screened, of which 8 met the inclusion criteria. We identified two distinct trends of resistance prevalence, which are dependent on frequency of AZM provision and baseline prevalence of resistance. We also demonstrated strong correlation between the prevalence of resistance at baseline and at 2-3 months (r=0.759). Although resistance to AZM inC. trachomatishas not been reported, resistance to this commonly used macrolide antibiotic in other diseases could compromise treatment. This should be considered when planning long-term trachoma control strategies.

scholarly journals Structural basis of a histidine-DNA nicking/joining mechanism for gene transfer and promiscuous spread of antibiotic resistance

2017 ◽  
Vol 114 (32) ◽  
pp. E6526-E6535 ◽  
Author(s):  
Radoslaw Pluta ◽  
D. Roeland Boer ◽  
Fabián Lorenzo-Díaz ◽  
Silvia Russi ◽  
Hansel Gómez ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Gene Transfer ◽  
Multidrug Resistant ◽  
High Energy ◽  
Structural Basis ◽  
Main Process ◽  
Bacterial Gene ◽  
Gram Positive Bacteria ◽  
Dna Nicking ◽  
Cell To Cell Transfer

Relaxases are metal-dependent nucleases that break and join DNA for the initiation and completion of conjugative bacterial gene transfer. Conjugation is the main process through which antibiotic resistance spreads among bacteria, with multidrug-resistant staphylococci and streptococci infections posing major threats to human health. The MOBV family of relaxases accounts for approximately 85% of all relaxases found in Staphylococcus aureus isolates. Here, we present six structures of the MOBV relaxase MobM from the promiscuous plasmid pMV158 in complex with several origin of transfer DNA fragments. A combined structural, biochemical, and computational approach reveals that MobM follows a previously uncharacterized histidine/metal-dependent DNA processing mechanism, which involves the formation of a covalent phosphoramidate histidine-DNA adduct for cell-to-cell transfer. We discuss how the chemical features of the high-energy phosphorus-nitrogen bond shape the dominant position of MOBV histidine relaxases among small promiscuous plasmids and their preference toward Gram-positive bacteria.

scholarly journals Inner-membrane GspF of the bacterial type II secretion system is a dimeric adaptor mediating pseudopilus biogenesis

2018 ◽  
Author(s):  
Wouter Van Putte ◽  
Tatjana De Vos ◽  
Wim Van Den Broeck ◽  
Henning Stahlberg ◽  
Misha Kudryashev ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Virulence Factors ◽  
Protein Complex ◽  
Secretion System ◽  
Structural Basis ◽  
Type Ii Secretion ◽  
Type Ii ◽  
Secretion Systems ◽  
Inner Membrane ◽  
Type Ii Secretion System

AbstractThe type II secretion system (T2SS), a protein complex spanning the bacterial envelope, is pivotal to bacterial pathogenicity. Central to T2SS function is the extrusion of protein cargos from the periplasm into the extracellular environment mediated by a pseudopilus and motorized by a cytosolic ATPase. GspF, an inner-membrane component of T2SS has long been considered to be a key player in this process, yet the structural basis of its role had remained elusive. Here, we employed single-particle electron microscopy based on XcpS (GspF) from the T2SS of pathogenicP. aeruginosastabilized by a nanobody, to show that XcpS adopts a dimeric structure mediated by its transmembrane helices. This assembly matches in terms of overall organization and dimensions the basal inner-membrane cassette of a T2SS machinery. Thus, GspF is poised to serve as an adaptor involved in the mediation of propeller-like torque generated by the motor ATPase to the secretion pseudopilus.Non-technical author summaryAntibiotic resistance by bacteria imposes a worldwide threat that can only be overcome through a multi-front approach: preventive actions and the parallel development of novel molecular strategies to combat antibiotic resistance mechanisms. One such strategy might focus on antivirulence drugs that prevent host invasion and spreading by pathogenic bacteria, without shutting down essential functions related to bacterial survival. The rationale behind such an approach is that it might limit selective pressure leading to slower evolutionary rates of resistant bacterial strains. Bacterial secretion systems are an appropriate target for such therapeutic approaches as their impairment will inhibit the secretion of a multitude of virulence factors. This study focuses on the structural characterization of one of the proteins residing in the inner-membrane cassette of the type II secretion system (T2SS), a multi-protein complex in multiple opportunistic pathogens that secretes virulence factors. The targeted protein is essential for the assembly of the pseudopilus, a rod-like supramolecular structure that propels the secretion of virulence factors by pathogenic Gram-negative bacteria. Our study crucially complements growing evidence supporting a rotational assembly model of the pseudopilus and contributes to a better understanding of the functioning of the T2SS and the related secretion systems. We envisage that such knowledge will facilitate targeting of these systems for therapeutic purposes.

scholarly journals Predicting Rifampicin Resistance Mutations in Bacterial RNA Polymerase Subunit Beta Based on Machine Learning Algorithms

2020 ◽  
Author(s):  
Qing Ning ◽  
Dali Wang ◽  
Fei Cheng ◽  
Yuheng Zhong ◽  
Qi Ding ◽  
...  
Keyword(s):  
Machine Learning ◽  
Antibiotic Resistance ◽  
Rna Polymerase ◽  
Binding Energies ◽  
Machine Learning Algorithms ◽  
New Drugs ◽  
Structural Basis ◽  
Resistance Mutations ◽  
Bacterial Rna ◽  
Majority Consensus

Abstract BackgroundMutations in an enzyme target are one of the most common mechanisms whereby antibiotic resistance arises. Identification of the resistance mutations in bacteria is essential for understanding the structural basis of antibiotic resistance and design of new drugs. However, the traditionally used experimental approaches to identify resistance mutations were usually labor-intensive and costly. ResultsWe present a machine learning (ML)-based classifier for predicting rifampicin (Rif) resistance mutations in bacterial RNA Polymerase subunit β (RpoB). A total of 66 resistance mutations were gathered from the literature to form positive dataset, while 53 residue variations of RpoB among a series of naturally occurring species were obtained as negative database. The features of the mutated RpoB and their binding energies with Rif were calculated through computational methods, and used as the mutation attributes for modelling. Classifiers based on four ML algorithms, i.e. decision tree, k nearest neighbors, naïve Bayes and supporting vector machine, were developed, which showed accuracy ranging from 0.69 to 0.76. A majority consensus approach was then used to obtain a new classifier based on the classifications of the four individual ML algorithms. The majority consensus classifier significantly improved the predictive performance, with accuracy, precision, recall and specificity of 0.83, 0.84, 0.86 and 0.83, respectively. ConclusionThe majority consensus classifier provides an alternative methodology for rapid identification of resistance mutations in bacteria, which may help with early detection of antibiotic resistance and new drug discovery.

scholarly journals Structural basis of resistance to lincosamide, streptogramin A, and pleuromutilin antibiotics by ABCF ATPases in Gram-positive pathogens

2020 ◽  
Author(s):  
Caillan Crowe-McAuliffe ◽  
Victoriia Murina ◽  
Kathryn Jane Turnbull ◽  
Marje Kasari ◽  
Merianne Mohamad ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Ribosomal Subunit ◽  
Structural Basis ◽  
Comparative Approach ◽  
Host Organism ◽  
Large Ribosomal Subunit ◽  
Gram Positive ◽  
Present Evidence ◽  
Gram Positive Bacteria ◽  
Peptidyltransferase Center

AbstractTarget protection proteins bind to antibiotic targets and confer resistance to the host organism. One class of such proteins, termed antibiotic resistance (ARE) ATP binding cassette (ABC) proteins of the F-subtype (ARE ABCFs), are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition by antibiotics that target the large ribosomal subunit. Using single-particle cryo-EM, we have solved the structure of ARE ABCF–ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a comparative approach to understanding how these proteins mediate antibiotic resistance on the ribosome. We present evidence of mechanistically diverse allosteric relays converging on a few peptidyltransferase center (PTC) nucleotides, and propose a general model of antibiotic resistance mediated by these ARE ABCFs.

scholarly journals Structural basis for antibiotic resistance mediated by the Bacillus subtilis ABCF ATPase VmlR

2018 ◽  
Vol 115 (36) ◽  
pp. 8978-8983 ◽  
Author(s):  
Caillan Crowe-McAuliffe ◽  
Michael Graf ◽  
Paul Huter ◽  
Hiraku Takada ◽  
Maha Abdelshahid ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Bacillus Subtilis ◽  
Binding Site ◽  
Pathogenic Bacteria ◽  
Small Subunit ◽  
Structural Basis ◽  
Abc Protein ◽  
Peptidyltransferase Center ◽  
A Site ◽  
Microbiological Analyses

Many Gram-positive pathogenic bacteria employ ribosomal protection proteins (RPPs) to confer resistance to clinically important antibiotics. In Bacillus subtilis, the RPP VmlR confers resistance to lincomycin (Lnc) and the streptogramin A (SA) antibiotic virginiamycin M (VgM). VmlR is an ATP-binding cassette (ABC) protein of the F type, which, like other antibiotic resistance (ARE) ABCF proteins, is thought to bind to antibiotic-stalled ribosomes and promote dissociation of the drug from its binding site. To investigate the molecular mechanism by which VmlR confers antibiotic resistance, we have determined a cryo-electron microscopy (cryo-EM) structure of an ATPase-deficient B. subtilis VmlR-EQ2 mutant in complex with a B. subtilis ErmDL-stalled ribosomal complex (SRC). The structure reveals that VmlR binds within the E site of the ribosome, with the antibiotic resistance domain (ARD) reaching into the peptidyltransferase center (PTC) of the ribosome and a C-terminal extension (CTE) making contact with the small subunit (SSU). To access the PTC, VmlR induces a conformational change in the P-site tRNA, shifting the acceptor arm out of the PTC and relocating the CCA end of the P-site tRNA toward the A site. Together with microbiological analyses, our study indicates that VmlR allosterically dissociates the drug from its ribosomal binding site and exhibits specificity to dislodge VgM, Lnc, and the pleuromutilin tiamulin (Tia), but not chloramphenicol (Cam), linezolid (Lnz), nor the macrolide erythromycin (Ery).

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