Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in
            <i>Enterobacteriaceae</i>
            : a Systematic Review of Current Reports

Mmatli, Masego; Mbelle, Nontombi Marylucy; Maningi, Nontuthuko Excellent; Sekyere, John Osei

doi:10.1128/msystems.00783-20

Cited by 61 publications

(106 citation statements)

References 206 publications

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“…The mcr-1 gene encodes a protein that is homologous to the phosphoethanolamine (PEtN) transferase enzyme involved in the LPS modification pathway. This finding of the plasmid-borne gene mcr-1 is quite significant considering that it could be acquired horizontally leading to the rapid development of polymyxin resistance (Ayoub Moubareck 2020 ; Mmatli et al 2020 ; Poirel et al 2017b ). As mcr-1 expression alone increases the MIC of polymyxin by 4- to 8-fold, a single step of acquisition of the plasmid can make the susceptible bacteria resistant.…”

Section: Polymyxins: the Last-resort Antibioticsmentioning

confidence: 99%

“…The polymyxin group of antibiotics discovered in 1947 from the bacterium Bacillus polymyxa are one such candidate. Till now, more than fifteen varieties of polymyxins have been isolated and characterized, among which the most prominent ones are polymyxin B and polymyxin E (also known as colistin) (Mmatli et al 2020 ; Nang et al 2021 ; Poirel et al 2017a ; Trimble et al 2016 ). The polymyxins exhibit significant inhibitory effect against the Gram-negative bacterial pathogens, therefore, it has emerged as an ultimate choice to target such pathogens that have already become resistant to the frontline antibiotics such as β-lactams, aminoglycosides, and the fluoroquinolones (Biswas et al 2012 ; Landman et al 2008 ; Mmatli et al 2020 ; Nang et al 2021 ; Poirel et al 2017a ).…”

Section: Polymyxins: the Last-resort Antibioticsmentioning

confidence: 99%

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Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions

Mohapatra¹,

Dwibedy²,

Padhy³

2021

J Biosci

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Infections caused by multi-drug resistant (MDR) bacterial pathogens are a leading cause of mortality and morbidity across the world. Indiscriminate use of broad-spectrum antibiotics has seriously affected this situation. With the diminishing discovery of novel antibiotics, new treatment methods are urgently required to combat MDR pathogens. Polymyxins, the cationic lipopeptide antibiotics, discovered more than half a century ago, are considered to be the last-line of antibiotics available at the moment. This antibiotic shows a great bactericidal effect against Gram-negative bacteria. Polymyxins primarily target the bacterial membrane and disrupt them, causing lethality. Because of their membrane interacting mode of action, polymyxins cause nephrotoxicity and neurotoxicity in humans, limiting their usability. However, recent modifications in their chemical structure have been able to reduce the toxic effects. The development of better dosing regimens has also helped in getting better clinical outcomes in the infections caused by MDR pathogens. Since the mid-1990s the use of polymyxins has increased manifold in clinical settings, resulting in the emergence of polymyxin-resistant strains. The risk posed by the polymyxin-resistant nosocomial pathogens such as the Enterobacteriaceae group, Pseudomonas aeruginosa , and Acinetobacter baumannii, etc. is very serious considering these pathogens are resistant to almost all available antibacterial drugs. In this review article, the mode of action of the polymyxins and the genetic regulatory mechanism responsible for the emergence of resistance are discussed. Specifically, this review aims to update our current understanding in the field and suggest possible solutions that can be pursued for future antibiotic development. As polymyxins primarily target the bacterial membranes, resistance to polymyxins arises primarily by the modification of the lipopolysaccharides (LPS) in the outer membrane (OM). The LPS modification pathways are largely regulated by the bacterial two-component signal transduction (TCS) systems. Therefore, targeting or modulating the TCS signalling mechanisms can be pursued as an alternative to treat the infections caused by polymyxin-resistant MDR pathogens. In this review article, this aspect is also highlighted.

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Section: Polymyxins: the Last-resort Antibioticsmentioning

confidence: 99%

Section: Polymyxins: the Last-resort Antibioticsmentioning

confidence: 99%

Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions

Mohapatra¹,

Dwibedy²,

Padhy³

2021

J Biosci

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“…The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.03.21259964 doi: medRxiv preprint 4 While there is still an ongoing global battle against acquired carbapenem resistance in GNB, polymyxin resistance is also emerging at a faster pace 23 , owing to the global increase in the use of polymyxins to treat carbapenem-resistant infections 14,15 . Polymyxin resistance is primarily mediated by a mobile colistin resistance (mcr) gene 14,15 , as well as by modification(s) in or loss of lipopolysaccharides (LPS) and increase in capsule production, which often prevents polymyxins from binding to the target site 23,24 . Polymyxins are positively charged antimicrobial peptides and they target negatively charged LPS of the bacterial outer membranes 25 .…”

Section: Introductionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted July 7, 2021. ; https://doi.org/10.1101/2021.07.03.21259964 doi: medRxiv preprint 5 regulates the pbgP operon 15 , which encode membrane enzymes that are responsible for the formation and addition Ara4N (4-amino-4deoxy-L-arabinose) to Lipid A . Such enzymes are EptA (phosphothanolamine) and ArnT (glycosyltransferase) and are responsible for the remodelling of the surface structure of the Lipid A by adding Ara4N to 4' position of the Lipid A .…”

Section: Introductionmentioning

confidence: 99%

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Phylogenomics, Epigenomics, Virulome, and Mobilome of Gram-negative Bacteria Co-resistant to Carbapenems and Polymyxins: A One-Health Systematic Review and Meta-analyses

2021

Preprint

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Gram-negative bacteria (GNB) continue to develop resistance against important antibiotics including last-resort ones such as carbapenems and polymyxins. An analysis of GNB with co-resistance to carbapenems and polymyxins from a One Health perspective is presented. Data of species name, country, source of isolation, resistance genes (ARGs), plasmid type, clones, and mobile genetic elements (MGEs) were deduced from 129 articles from January 2016 to March 2021. Available genomes and plasmids were obtained from PATRIC and NCBI. Resistomes and methylomes were analysed using BAcWGSTdb and REBASE whilst Kaptive was used to predict capsule typing. Plasmids and other MEGs were identified using MGE Finder and ResFinder. Phylogenetic analyses were done using RAxML and annotated with MEGA 7. A total of 877 isolates, 32 genomes and 44 plasmid sequences were analysed. Most of these isolates were reported in Asian countries and were isolated from clinical, animal, and environmental sources. Colistin resistance was mostly mediated by mgrB inactivation, while OXA-48/181 was the most reported carbapenemase. IncX and IncI were the most common plasmids hosting carbapenemases and mcr genes. The isolates were co-resistant to other antibiotics, with floR (chloramphenicol) and fosA3 (fosfomycin) being common; E. coli ST156 and K. pneumoniae ST258 strains were common globally. Virulence genes and capsular KL-types were also detected. Type I, II, III and IV restriction modification systems were detected, comprising various MTases and restriction enzymes. The escalation of highly resistant isolates drains the economy due to untreatable bacterial infections, which leads to increasing global mortality rates and healthcare costs.

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Optimization of a lysis method to isolate periplasmic proteins from Gram‐negative bacteria for clinical mass spectrometry

Cheon¹,

Lee²,

Yang³

et al. 2021

Proteomics Clinical Apps

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Purpose Clinical mass spectrometry requires a simple step process for sample preparation. This study aims to optimize the method for isolating periplasmic protein from Gram‐negative bacteria and apply to clinical mass spectrometry. Experimental Design The Klebsiella pneumoniae carbapenemase (KPC)‐producing E. coli standard cells were used for optimizing the osmotic shock (OS) lysis method. The supernatant from OS lysis was analysed by LC‐MS/MS and MALDI‐TOF MS. The effectiveness of the OS lysis method for KPC‐2‐producing Enterobacteriaceae clinical isolates were then confirmed by MALDI‐TOF MS. Results The optimized OS lysis using KPC‐2 producing E. coli standard cells showed a high yield of KPC‐2 protein and enriches periplasmic proteins. Compared with other lysis methods, the detection sensitivity of KPC‐2 protein significantly increased in MALDI‐TOF MS analysis. Nineteen clinical isolates were validated by MALDI‐TOF MS using the OS method, which also showed higher detection sensitivity compared to other lysis method (e.g., 1.5% n‐octyl‐β‐D‐glucopyranoside) (p < 0.001). Conclusions and Clinical Relevance This study provides a straightforward, rapid, affordable, and detergent‐free method for the analysis of periplasmic proteins from Enterobacteriaceae clinical isolates. This approach may contribute to MS‐based clinical diagnostics.

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Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in Enterobacteriaceae : a Systematic Review of Current Reports

Cited by 61 publications

References 206 publications

Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions

Polymyxins, the last-resort antibiotics: Mode of action, resistance emergence, and potential solutions

Phylogenomics, Epigenomics, Virulome, and Mobilome of Gram-negative Bacteria Co-resistant to Carbapenems and Polymyxins: A One-Health Systematic Review and Meta-analyses

Optimization of a lysis method to isolate periplasmic proteins from Gram‐negative bacteria for clinical mass spectrometry

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