scholarly journals Deciphering MCR-2 Colistin Resistance

mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Jian Sun ◽  
Yongchang Xu ◽  
Rongsui Gao ◽  
Jingxia Lin ◽  
Wenhui Wei ◽  
...  
Keyword(s):  
Public Health ◽  
Lipid A ◽  
Multidrug Resistant ◽  
Zinc Binding ◽  
Resistant Bacteria ◽  
Colistin Resistance ◽  
Gram Negative ◽  
Resistance Protein ◽  
Catalytic Motif ◽  
Potential Challenge

ABSTRACT Antibiotic resistance is a prevalent problem in public health worldwide. In general, the carbapenem β-lactam antibiotics are considered a final resort against lethal infections by multidrug-resistant bacteria. Colistin is a cationic polypeptide antibiotic and acts as the last line of defense for treatment of carbapenem-resistant bacteria. Very recently, a new plasmid-borne colistin resistance gene, mcr-2, was revealed soon after the discovery of the paradigm gene mcr-1, which has disseminated globally. However, the molecular mechanisms for MCR-2 colistin resistance are poorly understood. Here we show a unique transposon unit that facilitates the acquisition and transfer of mcr-2. Evolutionary analyses suggested that both MCR-2 and MCR-1 might be traced to their cousin phosphoethanolamine (PEA) lipid A transferase from a known polymyxin producer, Paenibacillus. Transcriptional analyses showed that the level of mcr-2 transcripts is relatively higher than that of mcr-1. Genetic deletions revealed that the transmembrane regions (TM1 and TM2) of both MCR-1 and MCR-2 are critical for their location and function in bacterial periplasm, and domain swapping indicated that the TM2 is more efficient than TM1. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) confirmed that all four MCR proteins (MCR-1, MCR-2, and two chimeric versions [TM1-MCR-2 and TM2-MCR-1]) can catalyze chemical modification of lipid A moiety anchored on lipopolysaccharide (LPS) with the addition of phosphoethanolamine to the phosphate group at the 4′ position of the sugar. Structure-guided site-directed mutagenesis defined an essential 6-residue-requiring zinc-binding/catalytic motif for MCR-2 colistin resistance. The results further our mechanistic understanding of transferable colistin resistance, providing clues to improve clinical therapeutics targeting severe infections by MCR-2-containing pathogens. IMPORTANCE Carbapenem and colistin are the last line of refuge in fighting multidrug-resistant Gram-negative pathogens. MCR-2 is a newly emerging variant of the mobilized colistin resistance protein MCR-1, posing a potential challenge to public health. Here we report transfer of the mcr-2 gene by a unique transposal event and its possible origin. Distribution of MCR-2 in bacterial periplasm is proposed to be a prerequisite for its role in the context of biochemistry and the colistin resistance. We also define the genetic requirement of a zinc-binding/catalytic motif for MCR-2 colistin resistance. This represents a glimpse of transferable colistin resistance by MCR-2. IMPORTANCE Carbapenem and colistin are the last line of refuge in fighting multidrug-resistant Gram-negative pathogens. MCR-2 is a newly emerging variant of the mobilized colistin resistance protein MCR-1, posing a potential challenge to public health. Here we report transfer of the mcr-2 gene by a unique transposal event and its possible origin. Distribution of MCR-2 in bacterial periplasm is proposed to be a prerequisite for its role in the context of biochemistry and the colistin resistance. We also define the genetic requirement of a zinc-binding/catalytic motif for MCR-2 colistin resistance. This represents a glimpse of transferable colistin resistance by MCR-2.

scholarly journals An amphipathic and cationic antimicrobial peptide kills colistin resistant Gram-negative pathogens in vivo

2021 ◽  
Author(s):  
Thomas T. Thomsen ◽  
Mette Kolpen ◽  
Vinoth Wigneswaran ◽  
Ulrik Kromann ◽  
Anna Ebbensgaard ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Lipid A ◽  
Multidrug Resistant ◽  
Colistin Resistance ◽  
Cationic Antimicrobial Peptide ◽  
Gram Negative ◽  
Excellent Activity ◽  
New Antibiotics ◽  
Charge Change

New antibiotics are needed against multidrug resistant Gram-negative pathogens that have compromised global health systems. Antimicrobial peptides are generally considered promising lead candidates for the next generation of antibiotics but have not fulfilled this expectation. Here we demonstrate activity of a cationic amphipathic undecapeptide (ChIP; Charge change Independent Peptide) against a wide panel of multidrug resistant Gram-negative pathogens. Importantly, the antimicrobial activity of ChIP is independent of the surface charge changes that confer colistin resistance through modification of Lipid A, while decreased activity of ChIP correlates with GlcN1 tri-acylation of Lipid A. In an in vivo peritonitis mouse model ChIP displays excellent activity against both colistin sensitive and resistant Escherichia coli and Acinetobacter baumannii strains.

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

Diagnostics ◽  
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.

scholarly journals A Review of Superbug: A Global Threat in Health Care System

2018 ◽  
Vol 4 (1) ◽  
pp. 25-28 ◽  
Author(s):  
Bhuiyan Mohammad Mahtab Uddin ◽  
Md Abdullah Yusuf ◽  
Zubair Ahmed Ratan
Keyword(s):  
Public Health ◽  
Health Problem ◽  
Antimicrobial Agents ◽  
Public Health Problem ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Major Public Health Problem ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Hospital Acquired

The rapid spread and dissemination of the multidrug-resistant bacteria worldwide represents a major public health problem. The development of antibiotics decreased the mortality among the human and animals leading to a better life expectancy. But the injudicious use of antimicrobials and selection pressure the microbes have developed resistance which became more prominent during last few decades. With the evolution of Methicilin-resistant Staphylococcus aureus (MRSA), Hospital-acquired MRSA, Communityacquired MRSA and MDR TB (Multidrug resistant tuberculosis) challenge for the clinicians have increased to a greater extent. The global emergence and dissemination of acquired carbapenemases among gram negative bacteria are considered a major public health problem. Gram-negative bacteria, most notably Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, are among the most important causes of serious hospital-acquired and community-onset bacterial infections in humans, and resistance to antimicrobial agents in these bacteria has become an increasingly relevant problem. Recent development in nanotechnology based drug delivery system may prove to be solution for combating these resistant bacteria. However policies and regulations for antibiotic use should be formulated to control the further development of resistance among the microbes.Bangladesh Journal of Infectious Diseases 2017;4(1):25-28

scholarly journals Current Update on Intrinsic and Acquired Colistin Resistance Mechanisms in Bacteria

2021 ◽  
Vol 8 ◽  
Author(s):  
Firdoos Ahmad Gogry ◽  
Mohammad Tahir Siddiqui ◽  
Insha Sultan ◽  
Qazi Mohd. Rizwanul Haq
Keyword(s):  
Pathogenic Bacteria ◽  
Lipid A ◽  
Resistance Mechanisms ◽  
New Drugs ◽  
Resistant Bacteria ◽  
Colistin Resistance ◽  
Gram Negative ◽  
Bacterial Surface ◽  
Resistance Determinants ◽  
Neisseria Meningitides

Colistin regained global interest as a consequence of the rising prevalence of multidrug-resistant Gram-negative Enterobacteriaceae. In parallel, colistin-resistant bacteria emerged in response to the unregulated use of this antibiotic. However, some Gram-negative species are intrinsically resistant to colistin activity, such as Neisseria meningitides, Burkholderia species, and Proteus mirabilis. Most identified colistin resistance usually involves modulation of lipid A that decreases or removes early charge-based interaction with colistin through up-regulation of multistep capsular polysaccharide expression. The membrane modifications occur by the addition of cationic phosphoethanolamine (pEtN) or 4-amino-l-arabinose on lipid A that results in decrease in the negative charge on the bacterial surface. Therefore, electrostatic interaction between polycationic colistin and lipopolysaccharide (LPS) is halted. It has been reported that these modifications on the bacterial surface occur due to overexpression of chromosomally mediated two-component system genes (PmrAB and PhoPQ) and mutation in lipid A biosynthesis genes that result in loss of the ability to produce lipid A and consequently LPS chain, thereafter recently identified variants of plasmid-borne genes (mcr-1 to mcr-10). It was hypothesized that mcr genes derived from intrinsically resistant environmental bacteria that carried chromosomal pmrC gene, a part of the pmrCAB operon, code three proteins viz. pEtN response regulator PmrA, sensor kinase protein PmrAB, and phosphotransferase PmrC. These plasmid-borne mcr genes become a serious concern as they assist in the dissemination of colistin resistance to other pathogenic bacteria. This review presents the progress of multiple strategies of colistin resistance mechanisms in bacteria, mainly focusing on surface changes of the outer membrane LPS structure and other resistance genetic determinants. New handier and versatile methods have been discussed for rapid detection of colistin resistance determinants and the latest approaches to revert colistin resistance that include the use of new drugs, drug combinations and inhibitors. Indeed, more investigations are required to identify the exact role of different colistin resistance determinants that will aid in developing new less toxic and potent drugs to treat bacterial infections. Therefore, colistin resistance should be considered a severe medical issue requiring multisectoral research with proper surveillance and suitable monitoring systems to report the dissemination rate of these resistant genes.

scholarly journals In vitro evolution of colistin resistance in the Klebsiella pneumoniae complex follows multiple evolutionary trajectories with variable effects on fitness and virulence characteristics

2020 ◽  
Author(s):  
Axel B. Janssen ◽  
Dennis J. Doorduijn ◽  
Grant Mills ◽  
Malbert R.C. Rogers ◽  
Marc J.M. Bonten ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Lipid A ◽  
Multidrug Resistant ◽  
Sensu Stricto ◽  
Cross Resistance ◽  
Gram Negative Bacteria ◽  
Colistin Resistance ◽  
Gram Negative ◽  
Evolutionary Trajectories

AbstractThe increasing prevalence of multidrug-resistant Gram-negative opportunistic pathogens, including Klebsiella pneumoniae, has led to a resurgence in the use of colistin as a last-resort drug. Colistin is a cationic lipopeptide antibiotic that selectively acts on Gram-negative bacteria through electrostatic interactions with anionic phosphate groups of the lipid A moiety of lipopolysaccharides (LPS). Colistin resistance in K. pneumoniae is mediated through loss of these phosphate groups, or modification with cationic groups (e.g. 4-amino-4-deoxy-L-arabinose (L-Ara4N), or phosphoethanolamine), but also hydroxylation of acyl-groups of lipid A. Here, we study the in vitro evolutionary trajectories towards colistin resistance in clinical K. pneumoniae complex strains (three K. pneumoniae sensu stricto strains and one K. variicola subsp. variicola strain) and their impact on fitness and virulence characteristics.Through population sequencing during the in vitro evolution experiment, we found that resistance develops through a combination of single nucleotide polymorphisms (SNPs), insertion and deletions (indels), and the integration of insertion sequence (IS) elements, affecting genes associated with LPS biosynthesis and modification, and capsule structures. The development of colistin resistance decreased the maximum growth rate of one K. pneumoniae sensu stricto strain, but not in the other three K. pneumoniae sensu lato strains. Colistin-resistant strains had lipid A modified through hydroxylation, palmitoylation, and L-Ara4N addition. Colistin-resistant K. pneumoniae sensu stricto strains exhibited cross-resistance to LL-37, in contrast to the K. variicola subsp. variicola strain that did not change in susceptibility to LL-37. Virulence, as determined in a Caenorhabditis elegans survival assay, was higher in two colistin-resistant strains.Our study suggests that nosocomial K. pneumoniae complex strains can rapidly develop colistin resistance de novo through diverse evolutionary trajectories upon exposure to colistin. This effectively shortens the lifespan of this last-resort antibiotic for the treatment of infections with multidrug-resistant Klebsiella.Author summaryBacteria that frequently cause infections in hospitalised patients are becoming increasingly resistant to antibiotics. Colistin is a positively charged antibiotic that is used for the treatment of infections with multidrug-resistant Gram-negative bacteria. Colistin acts by specifically interacting with the negatively charged LPS molecule in the outer membrane of Gram-negative bacteria. Colistin resistance is mostly mediated through modification of LPS to reduce its negative charge. Here, we use a laboratory evolution experiment to show that strains belonging to the Klebsiella pneumoniae complex, a common cause of multidrug-resistant hospital-acquired infections, can rapidly accumulate mutations that reduce the negative charge of LPS without an appreciable loss of fitness. Colistin resistance can lead to cross-resistance to an antimicrobial peptide of the human innate immune system, but can increase susceptibility to serum, and virulence in a nematode model. These findings show that extensively resistant K. pneumoniae complex strains may rapidly develop resistance to the last-resort antibiotic colistin via different evolutionary trajectories, while retaining their ability to cause infections.

scholarly journals CXC Chemokines Exhibit Bactericidal Activity against Multidrug-Resistant Gram-Negative Pathogens

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
Matthew A. Crawford ◽  
Debra J. Fisher ◽  
Lisa M. Leung ◽  
Sara Lomonaco ◽  
Christine Lascols ◽  
...  
Keyword(s):  
Lipid A ◽  
Bacterial Pathogens ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Colistin Resistance ◽  
Antibiotic Resistant ◽  
Carbapenem Resistant ◽  
Bactericidal Effects ◽  
Global Spread ◽  
Multiple Antibiotics

ABSTRACT The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens. IMPORTANCE As bacterial pathogens become resistant to multiple antibiotics, the infections they cause become increasingly difficult to treat. Carbapenem antibiotics provide an essential clinical barrier against multidrug-resistant bacteria; however, the dissemination of bacterial enzymes capable of inactivating carbapenems threatens the utility of these important antibiotics. Compounding this concern is the global spread of bacteria invulnerable to colistin, a polymyxin antibiotic considered to be a last line of defense against carbapenem-resistant pathogens. As the effectiveness of existing antibiotics erodes, it is critical to develop innovative antimicrobial therapies. To this end, we demonstrate that the chemokines CXCL9 and CXCL10 kill the most concerning carbapenem- and colistin-resistant pathogens. Our findings provide a unique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.” IMPORTANCE As bacterial pathogens become resistant to multiple antibiotics, the infections they cause become increasingly difficult to treat. Carbapenem antibiotics provide an essential clinical barrier against multidrug-resistant bacteria; however, the dissemination of bacterial enzymes capable of inactivating carbapenems threatens the utility of these important antibiotics. Compounding this concern is the global spread of bacteria invulnerable to colistin, a polymyxin antibiotic considered to be a last line of defense against carbapenem-resistant pathogens. As the effectiveness of existing antibiotics erodes, it is critical to develop innovative antimicrobial therapies. To this end, we demonstrate that the chemokines CXCL9 and CXCL10 kill the most concerning carbapenem- and colistin-resistant pathogens. Our findings provide a unique and timely foundation for therapeutic strategies capable of countering antibiotic-resistant “superbugs.”

scholarly journals A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening Acinetobacter baumannii

2021 ◽  
Author(s):  
Xukai Jiang ◽  
Nitin A. Patil ◽  
Mohammad A. K. Azad ◽  
Hasini Wickremasinghe ◽  
Heidi Yu ◽  
...  
Keyword(s):  
Public Health ◽  
Chemical Biology ◽  
Multidrug Resistant ◽  
Computational Approach ◽  
Gram Negative Bacteria ◽  
Global Public Health ◽  
Gram Negative ◽  
Life Threatening ◽  
New Generation ◽  
Novel Antibiotics

Multidrug-resistant Gram-negative bacteria have been an urgent threat to global public health. Novel antibiotics are desperately needed to combat these 'superbugs'.

scholarly journals Multidrug-resistant bacteria isolated from surgical site of dogs, surgeon's hands and operating room in a veterinary teaching hospital in Brazil

2021 ◽  
Author(s):  
Mareliza Possa de Menezes ◽  
Mariana Borzi ◽  
Mayara Ruaro ◽  
Marita Cardozo ◽  
Fernando Ávila ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
High Rate ◽  
Resistant Bacteria ◽  
Coagulase Negative Staphylococci ◽  
Gram Negative ◽  
Source Of Infection ◽  
The One ◽  
Clean Contaminated ◽  
In The Beginning ◽  
Coagulase Positive Staphylococci

Abstract The aim of this study was to evaluate the prevalence and antimicrobial resistance profile of Gram-positive cocci and Gram-negative bacilli isolated from the surgical environment. All samples were collected during the intraoperative period of clean/clean-contaminated (G1) and contaminated (G2) surgery. A total of 150 samples were collected from the surgical wound in the beginning (n = 30) and end (n = 30) of the procedure, surgeon’s hands before (n = 30) and after (n = 30) antisepsis and the surgical environment (n = 30). Forty-three isolates with morphological and biochemical characteristics of Staphylococcus spp. and 13 of Gram-negative bacilli were obtained. Coagulase-negative staphylococci (85.71% [18/21]), coagulase-positive staphylococci (9.52% [2/21]) and Pseudomonas spp. (47.52% [1/21]) in G1, and coagulase-negative staphylococci (40% [14/35]), coagulase-positive staphylococci (20% [7/35]), Proteus spp. (17.14% [6/35]), E. coli (8.57% [3/35]), Pseudomonas spp. (2.86% [1/35]) and Salmonella spp. (2.86 [1/35]) in G2 were more frequently isolated, and a high incidence of multidrug resistance was observed in coagulase-negative staphylococci (87.5% [28/32]), coagulase-positive staphylococci (100% [11/11]) and Gram-negative bacilli (76.92% [10/13]). Methicillin-resistant Staphylococcus spp. accounted for 83.72% (36/43) of the Staphylococcus strains. Gram-negative bacilli cefotaxime-resistance constituted 81.82% (9/11) and imipenem resistance constituted 53.85% (7/13). The high rate of resistance of commensal bacteria found in our study is worrying. Coagulase-negative staphylococci are community pathogens related to nosocomial infections in human and veterinary hospitals, their presence in healthy patients and in veterinary professionals represent an important source of infection in the one health context. Continuous surveillance and application of antimicrobial stewardship programs are essential in the fight against this threat.

First identification and Limited Dissemination of mcr-1 Colistin Resistance in Salmonella Isolates in Jiaxing

2021 ◽  
Author(s):  
Ping Li ◽  
Li Zhan ◽  
Henghui Wang ◽  
Wenjie Gao ◽  
Lei Gao ◽  
...  
Keyword(s):  
Public Health ◽  
Multidrug Resistance ◽  
Antimicrobial Resistance ◽  
Gastrointestinal Disease ◽  
Foodborne Pathogen ◽  
Multidrug Resistant ◽  
Colistin Resistance ◽  
Antimicrobial Resistance Genes ◽  
Genetic Features ◽  
Multidrug Resistant Strain

Salmonella , a major foodborne pathogen, causes severe gastrointestinal disease in people and animals worldwide. Plasmid-borne mcr-1 , which confers colistin resistance in Salmonella, has significant epidemiological interest for public health safety. Here, we report the first evidence of mcr-1 -mediated colistin resistance in one multidrug-resistant strain，namely 16062 in this study, from 355 Salmonella isolates collected for Jiaxing foodborne pathogen monitoring in Zhejiang Province in 2015–2019. In addition to colistin, 16062 displayed multidrug resistance to various antimicrobials (β-lactams, quinolone, sulfonamide, florfenicol, ampicillin, streptomycin, nalidixic acid, aminoglycoside, and trimethoprim-sulfamethox). The mcr-1 -carrying IncX4 plasmid (p16062-MCR) in this study shares a conserved structure with other mcr -IncX4 plasmids. We found that other antimicrobial-resistance genes ( aac(6')-Ib-cr , aadA1 , aadA2 , aph(3')-Ia , oqxA , oqxB , sul1 , and cmlA1 ) are located on p16062-cmlA, an atypical IncHI2 plasmid, in isolate 16062. This is the first identification of transferable colistin resistance in foodborne Salmonella isolate collected in Jiaxing city, the 5-year monitoring of which revealed limited dissemination. By determining the genetic features of the plasmid vehicle, the characteristics of transferable mcr genes circulating in isolates from Jiaxing are now clearer.

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