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

ABSTRACTThe spread of carbapenem- and polymyxin-resistant Enterobacteriaceae poses a significant threat to public health, challenging clinicians worldwide with limited therapeutic options. This review describes the current coding and noncoding genetic and transcriptional mechanisms mediating carbapenem and polymyxin resistance, respectively. A systematic review of all studies published in PubMed database between 2015 to October 2020 was performed. Journal articles evaluating carbapenem and polymyxin resistance mechanisms, respectively, were included. The search identified 171 journal articles for inclusion. Different New Delhi metallo-β-lactamase (NDM) carbapenemase variants had different transcriptional and affinity responses to different carbapenems. Mutations within the Klebsiella pneumoniae carbapenemase (KPC) mobile transposon, Tn4401, affect its promoter activity and expression levels, increasing carbapenem resistance. Insertion of IS26 in ardK increased imipenemase expression 53-fold. ompCF porin downregulation (mediated by envZ and ompR mutations), micCF small RNA hyperexpression, efflux upregulation (mediated by acrA, acrR, araC, marA, soxS, ramA, etc.), and mutations in acrAB-tolC mediated clinical carbapenem resistance when coupled with β-lactamase activity in a species-specific manner but not when acting without β-lactamases. Mutations in pmrAB, phoPQ, crrAB, and mgrB affect phosphorylation of lipid A of the lipopolysaccharide through the pmrHFIJKLM (arnBCDATEF or pbgP) cluster, leading to polymyxin resistance; mgrB inactivation also affected capsule structure. Mobile and induced mcr, efflux hyperexpression and porin downregulation, and Ecr transmembrane protein also conferred polymyxin resistance and heteroresistance. Carbapenem and polymyxin resistance is thus mediated by a diverse range of genetic and transcriptional mechanisms that are easily activated in an inducing environment. The molecular understanding of these emerging mechanisms can aid in developing new therapeutics for multidrug-resistant Enterobacteriaceae isolates.

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Characterization of resistance mechanisms of Enterobacter cloacae Complex co-resistant to carbapenem and colistin

BMC Microbiology ◽

10.1186/s12866-021-02250-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Shixing Liu ◽

Renchi Fang ◽

Ying Zhang ◽

Lijiang Chen ◽

Na Huang ◽

...

Keyword(s):

Lipid A ◽

Efflux Pump ◽

Resistance Mechanism ◽

Carbapenem Resistance ◽

Enterobacter Cloacae ◽

Resistance Mechanisms ◽

Colistin Resistance ◽

Carbapenem Resistant ◽

Horizontal Spread

Abstract Background The emergence of carbapenem-resistant and colistin-resistant ECC pose a huge challenge to infection control. The purpose of this study was to clarify the mechanism of the carbapenems and colistin co-resistance in Enterobacter cloacae Complex (ECC) strains. Results This study showed that the mechanisms of carbapenem resistance in this study are: 1. Generating carbapenemase (7 of 19); 2. The production of AmpC or ESBLs combined with decreased expression of out membrane protein (12 of 19). hsp60 sequence analysis suggested 10 of 19 the strains belong to colistin hetero-resistant clusters and the mechanism of colistin resistance is increasing expression of acrA in the efflux pump AcrAB-TolC alone (18 of 19) or accompanied by a decrease of affinity between colistin and outer membrane caused by the modification of lipid A (14 of 19). Moreover, an ECC strain co-harboring plasmid-mediated mcr-4.3 and blaNDM-1 has been found. Conclusions This study suggested that there is no overlap between the resistance mechanism of co-resistant ECC strains to carbapenem and colistin. However, the emergence of strain co-harboring plasmid-mediated resistance genes indicated that ECC is a potential carrier for the horizontal spread of carbapenems and colistin resistance.

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Problematic clinical isolates of Pseudomonas aeruginosa from the university hospitals in Sofia, Bulgaria: current status of antimicrobial resistance and prevailing resistance mechanisms

Journal of Medical Microbiology ◽

10.1099/jmm.0.46986-0 ◽

2007 ◽

Vol 56 (7) ◽

pp. 956-963 ◽

Cited By ~ 17

Author(s):

Tanya Strateva ◽

Vessela Ouzounova-Raykova ◽

Boyka Markova ◽

Albena Todorova ◽

Yulia Marteva-Proevska ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antimicrobial Agents ◽

Carbapenem Resistance ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Clinical Isolates ◽

Current Status ◽

University Hospitals ◽

Active Efflux ◽

Genes Encoding

A total of 203 clinical isolates of Pseudomonas aeruginosa was collected during 2001–2006 from five university hospitals in Sofia, Bulgaria, to assess the current levels of antimicrobial susceptibility and to evaluate resistance mechanisms to antipseudomonal antimicrobial agents. The antibiotic resistance rates against the following antimicrobials were: carbenicillin 93.1 %, azlocillin 91.6 %, piperacillin 86.2 %, piperacillin/tazobactam 56.8 %, ceftazidime 45.8 %, cefepime 48.9 %, cefpirome 58.2 %, aztreonam 49.8 %, imipenem 42.3 %, meropenem 45.5 %, amikacin 59.1 %, gentamicin 79.7 %, tobramycin 89.6 %, netilmicin 69.6 % and ciprofloxacin 80.3 %. A total of 101 of the studied P. aeruginosa isolates (49.8 %) were multidrug resistant. Structural genes encoding class A and class D β-lactamases showed the following frequencies: bla VEB-1 33.1 %, bla PSE-1 22.5 %, bla PER-1 0 %, bla OXA-groupI 41.3 % and bla OXA-groupII 8.8 %. IMP- and VIM-type carbapenemases were not detected. In conclusion, the studied clinical strains of P. aeruginosa were problematic nosocomial pathogens. VEB-1 extended-spectrum β-lactamases appear to have a significant presence among clinical P. aeruginosa isolates from Sofia. Carbapenem resistance was related to non-enzymic mechanisms such as a deficiency of OprD proteins and active efflux.

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Global evolutionary epidemiology, phylogeography and resistome dynamics of Citrobacter species, Enterobacter hormaechei, Klebsiella variicola, and Proteeae clones: A One Health analyses

10.1101/2020.05.21.20109504 ◽

2020 ◽

Author(s):

John Osei Sekyere ◽

Melese Abate Reta

Keyword(s):

Multidrug Resistant ◽

Resistance Mechanisms ◽

Global Risk ◽

Global Epidemiology ◽

Evolutionary Epidemiology ◽

Enterobacter Hormaechei ◽

Resistant Strains ◽

Species Specific ◽

Almost All ◽

Respective Species

AbstractBackground.The global epidemiology and resistomes dynamics of multidrug-resistant Citrobacter spp., Enterobacter hormaechei, Klebsiella variicola, morganella morganii, Proteus mirabilis and Providencia spp. have not been described, despite their importance as emerging opportunistic clinical pathogens.Methods.The genomes of the above-mentioned organisms were curated from PATRIC and NCBI and used for evolutionary epidemiology, phylogeography and resistome analyses. The phylogeny trees were drawn using RAXmL and edited with Figtree. The resistomes were curated from GenBank and the phylogeography was manually mapped.Results and conclusion.Mcr-9 and other mcr variants were highly prevalent in E. hormaechei subsp. and substantial in C. freundii whilst KPC, OXA-48, NDM, IMP, VIM, TEM, OXA and SHV were abundant in global E. hormaechei subsp., Citrobacter freundii, P. mirabilis, P. stuartii and P. rettgeri clones/clades. Species-specific ampCs were highly conserved in respective species whilst fluoroquinolones, aminoglycosides, macrolides, fosfomycin, chloramphenicol, tetracycline, sulphamethoxazole and trimethoprim resistance mechanisms were abundantly enriched in almost all clades of most of the species, making them extensively and pandrug resistant; K. variicola, C. amalonaticus and C, koseri had relatively few resistance genes. Vertical and horizontal resistome transmissions as well as local and international dissemination of strains evolving from common ancestors were observed, suggesting the anthroponotic, zoonotic, and food-/water-borne infectiousness of these pathogens. There is a global risk of pandrug resistant strains escalating local and international outbreaks of antibiotic-insensitive infections, initiating the dawn of a post-antibiotic era.

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A Molecular Perspective on Colistin and Klebsiella pneumoniae: Mode of Action, Resistance Genetics, and Phenotypic Susceptibility

Diagnostics ◽

10.3390/diagnostics11071165 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1165

Author(s):

Rita Elias ◽

Aida Duarte ◽

João Perdigão

Keyword(s):

Klebsiella Pneumoniae ◽

Mode Of Action ◽

Lipid A ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Drug Susceptibility Testing ◽

Gram Negative Bacteria ◽

Colistin Resistance ◽

Gram Negative

Klebsiella pneumoniae is a rod-shaped, encapsulated, Gram-negative bacteria associated with multiple nosocomial infections. Multidrug-resistant (MDR) K. pneumoniae strains have been increasing and the therapeutic options are increasingly limited. Colistin is a long-used, polycationic, heptapeptide that has regained attention due to its activity against Gram-negative bacteria, including the MDR K. pneumoniae strains. However, this antibiotic has a complex mode of action that is still under research along with numerous side-effects. The acquisition of colistin resistance is mainly associated with alteration of lipid A net charge through the addition of cationic groups synthesized by the gene products of a multi-genic regulatory network. Besides mutations in these chromosomal genes, colistin resistance can also be achieved through the acquisition of plasmid-encoded genes. Nevertheless, the diversity of molecular markers for colistin resistance along with some adverse colistin properties compromises the reliability of colistin-resistance monitorization methods. The present review is focused on the colistin action and molecular resistance mechanisms, along with specific limitations on drug susceptibility testing for K. pneumoniae.

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Mutational and acquired carbapenem resistance mechanisms in multidrug resistant Pseudomonas aeruginosa clinical isolates from Recife, Brazil

Memórias do Instituto Oswaldo Cruz ◽

10.1590/0074-02760150233 ◽

2015 ◽

Vol 110 (8) ◽

pp. 1003-1009 ◽

Cited By ~ 10

Author(s):

Felipe Lira de Sá Cavalcanti ◽

Cristina Rodríguez Mirones ◽

Elena Román Paucar ◽

Laura Álvarez Montes ◽

Tereza Cristina Leal-Balbino ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Carbapenem Resistance ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Clinical Isolates

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Evaluation of Tigecycline and Minocycline Susceptibility among Clinical Isolates of Carbapenem Resistant Acinetobacter Species

Journal of Evolution of Medical and Dental Sciences ◽

10.14260/jemds/2021/297 ◽

2021 ◽

Vol 10 (19) ◽

pp. 1408-1412

Author(s):

Asna Parveen ◽

Pratibha Bhat

Keyword(s):

Carbapenem Resistance ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Clinical Samples ◽

Acinetobacter Species ◽

Healthcare Settings ◽

Carbapenem Resistant ◽

Vitek 2 ◽

Key Words Carbapenem

BACKGROUND Acinetobacter species are important infectious agents worldwide especially in healthcare settings. It has the ability to develop various resistance mechanisms to various antibiotics. We wanted to study the role of tigecycline and minocycline in the treatment of multidrug resistant Acinetobacter species. METHODS 254 non-repetitive isolates of Acinetobacter species from various clinical samples like exudates, blood, sputum, urine were retrospectively studied. Antibiotic susceptibility testing was done by Vitek 2 compact system. Susceptibility of the carbapenem resistant isolates towards tigecycline and minocycline were analysed. RESULTS 205 (80.7 %) isolates were resistant to either of the carbapenem drugs and 49 (19.3 %) were sensitive to all the 3 carbapenems, namely imipenem, meropenem and doripenem. 54.1 % isolates were sensitive to tigecycline while sensitivity towards minocycline was 40.5 %. The degree of sensitive concordance in the susceptibility to minocycline and tigecycline against Acinetobacter species was 31.1 %, which indicated fair agreement statistically. 21.1 % isolates were resistant / intermediate to minocycline but sensitive to tigecycline. Only 9.4 % isolates which were resistant to tigecycline were sensitive to minocycline. CONCLUSIONS The results of the present study have demonstrated that minocycline and tigecycline are effective against the carbapenem resistant Acinetobacter species. Tigecycline can be considered as a therapeutic agent for the treatment of multidrug resistant Acinetobacter which are otherwise difficult to inhibit using other antibiotics. KEY WORDS Carbapenem Resistance, Tigecycline, Minocycline, Antimicrobial Resistance

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Role of efflux pump and OprD porin expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates

The Journal of Infection in Developing Countries ◽

10.3855/jidc.9486 ◽

2018 ◽

Vol 12 (01) ◽

pp. 001-008 ◽

Cited By ~ 4

Author(s):

Tuba Muderris ◽

Rıza Durmaz ◽

Birsen Ozdem ◽

Tuba Dal ◽

Ozlem Unaldı ◽

...

Keyword(s):

Efflux Pump ◽

Carbapenem Resistance ◽

High Sensitivity ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Clonal Relationship ◽

Pfge Typing ◽

Reverse Transcription Pcr ◽

Carbapenem Resistant ◽

Relationship Of

Introduction: In recent years, the prevalence of multidrug-resistant P. aeruginosa has remarkably increased. Thus, we wanted to investigate the carbapenem resistance mechanisms and clonal relationship among 80 carbapenem-resistant P. aeruginosa strains. Methodology: Carbapenemase production was detected using the Modified Hodge Test (MHT), EDTA combined disc method (ECD), and PCR. Expression levels of efflux and porin genes were mesured by real-time reverse transcription PCR. Clonal relationship of the isolates was investigated by pulsed-field gel electrophoresis (PFGE). Results: Carbapenemase production was detected in 7.5% of the isolates with MHT/ECD tests and in 11.3% of the isolates with PCR. Although the specificity of MHT/ECD was high, the sensitivitivity was low. oprD downregulation and mexB, mexY, and mexD overexpression were demonstrated in 55%, 16.3%, 2.5%, and 2.5% of the isolates, respectively. Multiple carbapenem resistance mechanisms were found in nearly a quarter of the isolates. PFGE typing of the 80 P. aeruginosa isolates yielded 61 different patterns. A total of 29 isolates (36.3%) were classified in 10 clusters, containing 2 to 7 strains. We could not find a strict relationship between PFGE profile and carbapenem resistance mechanisms. Conclusions: Although oprD downregulation and MexAB-OprM overexpression were the most common mechanisms, carbapenem resistance was associated with multiple mechanisms in the study. MHT/ECD tests should not be used alone for investigation of carbapenemase production in P. aeruginosa. Rapid tests with high sensitivity and specificity should be developed for the detection of carbapenemase production in P. aeruginosa.

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The Burden of the Serious and Difficult-to-Treat Infections and a New Antibiotic Available: Cefiderocol

Frontiers in Pharmacology ◽

10.3389/fphar.2020.578823 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yasaman Taheri ◽

Nataša Joković ◽

Jelena Vitorović ◽

Oliver Grundmann ◽

Alfred Maroyi ◽

...

Keyword(s):

Bacterial Infections ◽

Treatment Options ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Antimicrobial Treatment ◽

Bacterial Cells ◽

Gram Negative ◽

Pubmed Database ◽

Severe Infections ◽

Unique Cell

Background: Infection is a disease that can occur due to the entrance of a virus, bacteria, and other infectious agents. Cefiderocol is innovative cephalosporin drug that belongs to a special class of antibiotics, sideromycins, which are taken up by bacterial cells through active transport. The unique cell entry and stability to β-lactamases allow cefiderocol to overcome the most common resistance mechanisms in Gram-negative bacteria.Objective: This article aims to highlight the therapeutic efficacy, safety and tolerability of cefiderocol, with a focus on the FDA label.Methods: The pharmacological properties of cefiderocol are also summarized. In this review, we conducted literature research on the PubMed database using the following keywords: “antimicrobial treatment”, “new antibiotic”, “cefiderocol”, “siderophore cephalosporin”; “multidrug-resistant”, “Gram-negative bacilli”, “critically ill patients”; “severe bacterial infections”.Results: There were identified the most relevant data about the pathophysiology of serious bacterial infections, antibacterial mechanism of action, microbiology, mechanisms of resistance, pharmacokinetic and pharmacodynamic properties of cefiderocol.Conclusion: The results highlighted there appeared to be clinical benefit from cefiderocol in the treatment of infections caused by Gram-negative aerobic microorganisms in adult patients with severe infections and limited treatment options.

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Heterogeneous resistance to colistin in Enterobacter cloacae complex due to a new small transmembrane protein

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz236 ◽

2019 ◽

Vol 74 (9) ◽

pp. 2551-2558 ◽

Cited By ~ 6

Author(s):

Liang Huang ◽

Yu Feng ◽

Zhiyong Zong

Keyword(s):

Rna Sequencing ◽

Insertional Mutagenesis ◽

Lipid A ◽

Efflux Pump ◽

Gene Knockout ◽

Transmembrane Protein ◽

Resistance Mechanisms ◽

Clinical Strain ◽

Gene Encoding ◽

Inner Membrane Protein

Abstract Background Enterobacter strains can display heterogeneous resistance (heteroresistance) to colistin but the mechanisms remain largely unknown. We investigated potential mechanisms of colistin heteroresistance in an Enterobacter clinical strain, WCHECl-1060, and found a new mechanism. Methods Strain WCHECl-1060 was subjected to WGS to identify known colistin resistance mechanisms. Tn5 insertional mutagenesis, gene knockout and complementation and shotgun cloning were employed to investigate unknown colistin heteroresistance mechanisms. RNA sequencing was performed to link the newly identified mechanism with known ones. Results We showed that the phoP gene [encoding part of the PhoP-PhoQ two-component system (TCS)], the dedA(Ecl) gene (encoding an inner membrane protein of the DedA family) and the tolC gene (encoding part of the AcrAB-TolC efflux pump) are required for colistin heteroresistance. We identified a new gene, ecr, encoding a 72 amino acid transmembrane protein, which was able to mediate colistin heteroresistance. We then performed RNA sequencing and transcriptome analysis and found that in the presence of ecr the expression of phoP and the arnBCADTEF operon, which synthesizes and transfers l-Ara4N to lipid A, was increased significantly. Conclusions The small protein encoded by ecr represents a new colistin heteroresistance mechanism and is likely to mediate colistin heteroresistance via the PhoP-PhoQ TCS to act on the arnBCADTEF operon.

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Carbapenem-resistance mechanisms of multidrug-resistant Pseudomonas aeruginosa

Journal of Medical Microbiology ◽

10.1099/jmm.0.058354-0 ◽

2013 ◽

Vol 62 (9) ◽

pp. 1317-1325 ◽

Cited By ~ 23

Author(s):

Ester Fusté ◽

Lídia López-Jiménez ◽

Concha Segura ◽

Eusebio Gainza ◽

Teresa Vinuesa ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Outer Membrane ◽

Antimicrobial Agents ◽

Efflux Pump ◽

Carbapenem Resistance ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Class 1 Integron ◽

Carbonyl Cyanide ◽

Class 1

Clonal dissemination of multidrug-resistant Pseudomonas aeruginosa (MDRPA) is a major concern worldwide. The aim of this study was to explore the mechanisms leading to the carbapenem resistance of an MDRPA clone. Isolates were obtained from a surgical wound, sputum, urine and a blood culture. Pulsed-field gel electrophoresis (PFGE) showed high genomic homogeneity of these isolates and confirmed the circulation of an endemic clone belonging to serotype O4. Outer membrane protein (OMP) bands were visualized by SDS-PAGE, meropenem accumulation was measured in a bioassay and integrons were detected by PCR. Efflux pumps were studied for several antimicrobial agents and synergic combinations thereof in the presence or absence of both carbonyl cyanide m-chlorophenylhydrazone (CCCP) and Phe-Arg-β-naphthylamide (PAβN) at final concentrations of 10 and 40 mg l−1, respectively. On OMP electrophoretic profiles, MDRPA showed a reduction of outer membrane porin D (OprD) and PCR demonstrated the presence of a class 1 integron with a cassette encoding aminoglycoside adenyltransferase B (aadB). Meropenem accumulation was slightly higher in bacilli than in the filamentous cells that formed in the presence of antibiotics. Overexpression of the efflux pump MexAB-OprM and a functional MexXY-OprM were detected in all isolates.

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