Genetic basis of molecular mechanisms in β-lactam resistant gram-negative bacteria. - Related Documents




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484401.0000Genetic basis of molecular mechanisms in β-lactam resistant gram-negative bacteria. Antibiotic-resistant bacteria are considered one of the major global threats to human and animal health. The most harmful among the resistant bacteria are β-lactamase producing Gram-negative species (β-lactamases). β-lactamases constitute a paradigm shift in the evolution of antibiotic resistance. Therefore, it is imperative to present a comprehensive review of the mechanisms responsible for developing antimicrobial resistance. Resistance due to β-lactamases develops through a variety of mechanisms, and the number of resistant genes are involved that can be transferred between bacteria, mostly via plasmids. Over time, these new molecular-based resistance mechanisms have been progressively disclosed. The present review article provides information on the recent findings regarding the molecular mechanisms of resistance to β-lactams in Gram-negative bacteria, including CTX-M-type ESBLs with methylase activity, plasmids harbouring phages with β-lactam resistance genes, the co-presence of β-lactam resistant genes of unique combinations and the presence of β-lactam and non-β-lactam antibiotic-resistant genes in the same bacteria. Keeping in view, the molecular level resistance development, multifactorial and coordinated measures may be taken to counter the challenge of rapidly increasing β-lactam resistance.202134119627
484510.9999The changing epidemiology of resistance. Antibiotic resistance is now a linked global problem. Dispersion of successful clones of multidrug resistant (MDR) bacteria is common, often via the movement of people. Local evolution of MDR bacteria is also important under the pressure of excessive antibiotic use, with horizontal gene transfer providing the means by which genes such as bla(CTX-M) spread amongst different bacterial species and strains. Beta-lactamase production is a common resistance mechanism in Gram-negative bacteria, and the rapid dissemination of novel genes reflects their evolution under the selective pressure of antibiotic usage. Many Enterobacteriaceae now carry broad-spectrum beta-lactamases such as CTX-M, with particular genotypes associated with different geographical regions. The spread of these enzymes has compromised the clinical utility of a number of beta-lactam classes and with the spread of genes such as bla(KPC), carbapenems may be increasingly compromised in the future. High-level fluoroquinolone resistance (mainly caused by gyrA mutations) has also been shown to be associated with CTX-M and CMY-type enzymes, commonly due to co-carriage on conjugative plasmids of the gene for the aminoglycoside-inactivating enzyme AAC-6(1)-Ib-cr and qnr genes (which confer low-level resistance), allowing the easy selection of gyrA mutants in the host strain. Resistance in Gram-positive bacteria is also widely distributed and increasing, with the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) blurring the distinction between hospital and community strains. Antibiotic use and environmental factors all have a role in the emergence and spread of resistance. This article reviews some of the new mechanisms and recent trends in the global spread of MDR bacteria.200919675017
484720.9999Escherichia coli β-Lactamases: What Really Matters. Escherichia coli strains belonging to diverse pathotypes have increasingly been recognized as a major public health concern. The β-lactam antibiotics have been used successfully to treat infections caused by pathogenic E. coli. However, currently, the utility of β-lactams is being challenged severely by a large number of hydrolytic enzymes - the β-lactamases expressed by bacteria. The menace is further compounded by the highly flexible genome of E. coli, and propensity of resistance dissemination through horizontal gene transfer and clonal spread. Successful management of infections caused by such resistant strains requires an understanding of the diversity of β-lactamases, their unambiguous detection, and molecular mechanisms underlying their expression and spread with regard to the most relevant information about individual bacterial species. Thus, this review comprises first such effort in this direction for E. coli, a bacterial species known to be associated with production of diverse classes of β-lactamases. The review also highlights the role of commensal E. coli as a potential but under-estimated reservoir of β-lactamases-encoding genes.201627065978
486230.9999Genetic Factors That Contribute to Antibiotic Resistance through Intrinsic and Acquired Bacterial Genes in Urinary Tract Infections. The overprescribing and misuse of antibiotics have led to the rapid development of multidrug-resistant bacteria, such as those that cause UTIs. UTIs are the most common outpatient infections and are mainly caused by Escherichia coli and Klebsiella spp., although some Gram-positive bacteria, such as Pseudomonas aeruginosa, have been isolated in many cases. The rise of antimicrobial-resistant bacteria is a major public health concern, as it is predicted to lead to increased healthcare costs and poor patient outcomes and is expected to be the leading cause of global mortality by 2050. Antibiotic resistance among bacterial species can arise from a myriad of factors, including intrinsic and acquired resistance mechanisms, as well as mobile genetic elements, such as transposons, integrons, and plasmids. Plasmid-mediated resistance is of major concern as drug-resistance genes can quickly and efficiently spread across bacterial species via horizontal gene transfer. The emergence of extended-spectrum β-lactamases (ESBLs) such as NDM-1, OXA, KPC, and CTX-M family members has conferred resistance to many commonly used antibiotics in the treatment of UTIs, including penicillins, carbapenems, cephalosporins, and sulfamethoxazole. This review will focus on plasmid-mediated bacterial genes, especially those that encode ESBLs, and how they contribute to antibiotic resistance. Early clinical detection of these genes in patient samples will provide better treatment options and reduce the threat of antibiotic resistance.202337374909
502840.9999The Current Burden of Carbapenemases: Review of Significant Properties and Dissemination among Gram-Negative Bacteria. Carbapenemases are β-lactamases belonging to different Ambler classes (A, B, D) and can be encoded by both chromosomal and plasmid-mediated genes. These enzymes represent the most potent β-lactamases, which hydrolyze a broad variety of β-lactams, including carbapenems, cephalosporins, penicillin, and aztreonam. The major issues associated with carbapenemase production are clinical due to compromising the activity of the last resort antibiotics used for treating serious infections, and epidemiological due to their dissemination into various bacteria across almost all geographic regions. Carbapenemase-producing Enterobacteriaceae have received more attention upon their first report in the early 1990s. Currently, there is increased awareness of the impact of nonfermenting bacteria, such as Acinetobacter baumannii and Pseudomonas aeruginosa, as well as other Gram-negative bacteria that are carbapenemase-producers. Outside the scope of clinical importance, carbapenemases are also detected in bacteria from environmental and zoonotic niches, which raises greater concerns over their prevalence, and the need for public health measures to control consequences of their propagation. The aims of the current review are to define and categorize the different families of carbapenemases, and to overview the main lines of their spread across different bacterial groups.202032316342
993250.9999Beta-lactam resistance mechanisms in gram-negative bacteria. Beta-lactam antibiotics are commonly used to treat a variety of bacterial infections. Gram-negative bacteria have evolved several resistance mechanisms including altered permeability and beta-lactamase production. New trends in resistance are emerging amongst clinical isolates which may reflect the choice of beta-lactam employed.19862856616
486360.9999Carbapenem Resistance in Gram-Negative Bacteria: The Not-So-Little Problem in the Little Red Dot. Singapore is an international travel and medical hub and faces a genuine threat for import and dissemination of bacteria with broad-spectrum resistance. In this review, we described the current landscape and management of carbapenem resistance in Gram-negative bacteria (GNB) in Singapore. Notably, the number of carbapenem-resistant Enterobacteriaceae has exponentially increased in the past two years. Resistance is largely mediated by a variety of mechanisms. Polymyxin resistance has also emerged. Interestingly, two Escherichia coli isolates with plasmid-mediated mcr-1 genes have been detected. Evidently, surveillance and infection control becomes critical in the local setting where resistance is commonly related to plasmid-mediated mechanisms, such as carbapenemases. Combination antibiotic therapy has been proposed as a last-resort strategy in the treatment of extensively drug-resistant (XDR) GNB infections, and is widely adopted in Singapore. The diversity of carbapenemases encountered, however, presents complexities in both carbapenemase detection and the selection of optimal antibiotic combinations. One unique strategy introduced in Singapore is a prospective in vitro combination testing service, which aids physicians in the selection of individualized combinations. The outcome of this treatment strategy has been promising. Unlike countries with a predominant carbapenemase type, Singapore has to adopt management strategies which accounts for diversity in resistance mechanisms.201627681907
486170.9999The Challenge of Global Emergence of Novel Colistin-Resistant Escherichia coli ST131. Escherichia coli ST131 is one of the high-risk multidrug-resistant clones with a global distribution and the ability to persist and colonize in a variety of niches. Carbapenemase-producing E. coli ST131 strains with the ability to resist last-line antibiotics (i.e., colistin) have been recently considered a significant public health. Colistin is widely used in veterinary medicine and therefore, colistin-resistant bacteria can be transmitted from livestock to humans through food. There are several mechanisms of resistance to colistin, which include chromosomal mutations and plasmid-transmitted mcr genes. E. coli ST131 is a great model organism to investigate the emergence of superbugs. This microorganism has the ability to cause intestinal and extraintestinal infections, and its accurate identification as well as its antibiotic resistance patterns are vitally important for a successful treatment strategy. Therefore, further studies are required to understand the evolution of this resistant organism for drug design, controlling the evolution of other nascent emerging pathogens, and developing antibiotic stewardship programs. In this review, we will discuss the importance of E. coli ST131, the mechanisms of resistance to colistin as the last-resort antibiotic against resistant Gram-negative bacteria, reports from different regions regarding E. coli ST131 resistance to colistin, and the most recent therapeutic approaches against colistin-resistance bacteria.202133913748
484380.9999The Efficacy of Isolated Bacteriophages from Pig Farms against ESBL/AmpC-Producing Escherichia coli from Pig and Turkey Farms. Extended-spectrum β-lactamases (ESBLs) and AmpC β-lactamases are plasmid (but also chromosomally) encoded enzymes found in Enterobacteriaceae, determining resistance to a variety of important antibiotics including penicillins, cephalosporins, and monobactams. In recent decades, the prevalence of ESBL/AmpC-producing bacteria has increased rapidly across the world. Here, we evaluate the potential use of bacteriophages in terms of a reduction of antibiotic-resistant bacteria in healthy animals. The aim of our studies was to isolate bacteriophages capable of destroying ESBL/AmpC-producing Escherichia coli isolated from livestock habitats. The efficacy of isolated phages against ESBL/AmpC E. coli strains varies, but creation of a phage cocktail with broad activity spectrum is possible. This may indicate that the role of phages may not be limited to phage therapy, but bacterial viruses may also be applied against spread of bacteria with antibiotic resistance genes in the environment. We also addressed the hypothesis, that phages, effective for therapeutic purposes may be isolated from distant places and even from different environments other than the actual location of the targeted bacteria. This may be beneficial for practical purposes, as the construction of effective phage preparations does not require access to disease outbreaks.201728405193
483990.9999beta-Lactamases: protein evolution in real time. The evolution and spread of bacteria resistant to beta-lactam antibiotics has progressed at an alarming rate. Bacteria may acquire resistance to a given drug by mutation of pre-existing genes or by the acquisition of new genes from other bacteria. One ongoing example of these mechanisms is the evolution of new variants of the TEM and SHV beta-lactamases with altered substrate specificity.19989746943
4846100.9999Mobile fosfomycin resistance genes in Enterobacteriaceae-An increasing threat. Antimicrobial resistance is one of the major threats to the health and welfare of both humans and animals. The shortage of new antimicrobial agents has led to the re-evaluation of old antibiotics such as fosfomycin as a potential regimen for treating multidrug-resistant bacteria especially extended-spectrum-beta-lactamase- and carbapenemase-producing Enterobacteriaceae. Fosfomycin is a broad-spectrum bactericidal antibiotic that inhibits the initial step of the cell wall biosynthesis. Fosfomycin resistance can occur due to mutation in the drug uptake system or by the acquisition of fosfomycin-modifying enzymes. In this review, we focus on mobile fosfomycin-resistant genes encoding glutathione-S-transferase which are mainly responsible for fosfomycin resistance in Enterobacteriaceae, that is, fosA and its subtypes, fosC2, and the recently described fosL1-L2. We summarized the proposed origins of the different resistance determinants and highlighted the different plasmid types which are attributed to the dissemination of fosfomycin-modifying enzymes. Thereby, IncF and IncN plasmids play a predominant role. The detection of mobile fosfomycin-resistant genes in Enterobacteriaceae has increased in recent years. Similar to the situation in (East) Asia, the most frequently detected fosfomycin-resistant gene in Europe is fosA3. Mobile fosfomycin-resistant genes have been detected in isolates of human, animal, food, and environmental origin which leads to a growing concern regarding the risk of spread of such bacteria, especially Escherichia coli and Salmonella, at the human-animal-environment interface.202033128341
4877110.9999Carbapenemase-producing Gram-negative bacteria in aquatic environments: a review. Antibiotic resistance is one of the greatest public-health challenges worldwide, especially with regard to Gram-negative bacteria (GNB). Carbapenems are the β-lactam antibiotics of choice with the broadest spectrum of activity and, in many cases, are the last-resort treatment for several bacterial infections. Carbapenemase-encoding genes, mainly carried by mobile genetic elements, are the main mechanism of resistance against carbapenems in GNB. These enzymes exhibit a versatile hydrolytic capacity and confer resistance to most β-lactam antibiotics. After being considered a clinical issue, increasing attention is being giving to the dissemination of such resistance mechanisms in the environment and especially through water. Aquatic environments are among the most significant microbial habitats on our planet, known as a favourable medium for antibiotic gene transfer, and they play a crucial role in the huge spread of drug resistance in the environment and the community. In this review, we present current knowledge regarding the spread of carbapenemase-producing isolates in different aquatic environments, which may help the implementation of control and prevention strategies against the spread of such dangerous resistant agents in the environment.202133895415
9928120.9999The emergence and implications of metallo-beta-lactamases in Gram-negative bacteria. The increase in Gram-negative broad-spectrum antibiotic resistance is worrisome, particularly as there are few, if any, ''pipeline'' antimicrobial agents possessing suitable activity against Pseudomonas spp. or Acinetobacter spp. The increase in resistance will be further enhanced by the acquisition of metallo-beta-lactamase (MBL) genes that can potentially confer broad-spectrum beta-lactam resistance. These genes encode enzymes that can hydrolyse all classes of beta-lactams and the activity of which cannot be neutralised by beta-lactamase inhibitors. MBL genes are often associated with aminoglycoside resistant genes and thus bacteria that possess MBL genes are often co-resistant to aminoglycosides, further compromising therapeutic regimes. Both types of genes can be found as gene cassettes carried by integrons that in turn are embedded within transposons providing a highly ambulatory genetic element. The dissemination of MBL genes is typified by the spread of blaVIM-2, believed to originate from a Portuguese patient in 1995, and is now present in over 20 counties. The increase in international travel is likely to be a contributory factor for the ascendancy of mobile MBL genes as much as the mobility among individual bacteria. Fitness, acquisition and host dependency are key areas that need to be addressed to enhance our understanding of how antibiotic resistance spreads. There is also a pressing need for new, and hopefully novel, compounds active against pan-resistant Gram-negative bacteria--a growing problem that needs to be addressed by both government and industry.200516209700
4868130.9999Extended spectrum β-lactamases, carbapenemases and mobile genetic elements responsible for antibiotics resistance in Gram-negative bacteria. Infectious diseases due to Gram-negative bacteria are a leading cause of morbidity and mortality worldwide. Antimicrobial agents represent one major therapeutic tools implicated to treat these infections. The misuse of antimicrobial agents has resulted in the emergence of resistant strains of Gram-negatives in particular Enterobacteriaceae and non-fermenters; they have an effect not only on a human but on the public health when bacteria use the resistance mechanisms to spread in the hospital environment and to the community outside the hospitals by means of mobile genetic elements. Gram-negative bacteria have become increasingly resistant to antimicrobial agents. They have developed several mechanisms by which they can withstand to antimicrobials, these mechanisms include the production of Extended-spectrum β-lactamases (ESBLs) and carbapenemases, furthermore, Gram-negative bacteria are now capable of spreading such resistance between members of the family Enterobacteriaceae and non-fermenters using mobile genetic elements as vehicles for such resistance mechanisms rendering antibiotics useless. Therefore, addressing the issue of mechanisms of antimicrobial resistance is considered one of most urgent priorities. This review will help to illustrate different resistance mechanisms; ESBLs, carbapenemases encoded by genes carried by mobile genetic elements, which are used by Gram-negative bacteria to escape antimicrobial effect.201322667455
4314140.9999Cephalosporin resistance among animal-associated Enterobacteria: a current perspective. Beta-lactam antimicrobials are an important class of drugs used for the treatment of infection. Resistance can arise by several mechanisms, including the acquisition of genes encoding beta-lactamases from other bacteria, alterations in cell membrane permeability and over expression of endogenous beta-lactamases. The acquisition of beta-lactamase resistance genes by both Salmonella and Escherichia coli appears to be on the rise, which may pose potential problems for the treatment of infections in both human and animal medicine. The prudent use of clinically important antimicrobials is therefore critical to maintain their effectiveness. Where possible, the use of newer generation cephalosporins should be limited in veterinary medicine.200515954857
4875150.9999An Overview of the Genetic Mechanisms of Colistin-Resistance in Bacterial Pathogens: An Indian Perspective. Colistin resistance in bacteria is a growing global issue, given its role as a critical last-resort antibiotic, particularly for treating Gram-negative bacterial infections. Pathogens adopt multiple resistance mechanisms, mediated either by plasmids or chromosomal changes. Some of the most frequently observed strategies include the occurrence of plasmid-borne mobile colistin resistance (mcr) genes, enhanced efflux pump activity, mutations in the regulatory systems, and alterations in the lipid A structure. This article provides an overview of the studies investigating the genetic mechanisms underlying colistin resistance in nosocomial Gram-negative bacteria from India. A total of 37 studies were identified through online searches across various databases, including PubMed, ScienceDirect, and Web of Science. These studies were reviewed to examine bacterial species and their mechanisms of colistin resistance. Over 26 (70.27%) studies were focused on Klebsiella pneumoniae. The most commonly reported mechanism of colistin resistance involved mutations in the two-component systems pmrAB and phoPQ. Plasmid-mediated colistin-resistant mcr genes were identified in 22 studies (18.18%). Four studies reported the overexpression of efflux pump genes as a mechanism of colistin resistance. This article provides a comprehensive summary of these studies, emphasizing the presence of diverse resistance mechanisms across various pathogens. It underscores the necessity for future genomic research on a broader range of pathogens to investigate the prevalence of different mechanisms of colistin resistance in the various regions of India.202540078264
4860160.9999The rise of carbapenem-resistant Acinetobacter baumannii. Acinetobacter spp. are Gram-negative bacteria that have become one of the most difficult pathogens to treat. The species A. baumannii, largely unknown 30 years ago, has risen to prominence particularly because of its ability to cause infections in immunocompromised patients. It is now a predominant pathogen in many hospitals as it has acquired resistance genes to virtually all antibiotics capable of treating Gram-negative bacteria, including the fluoroquinolones and the cephalosporins. Some members of the species have accumulated these resistance genes in large resistance islands, located in a "hot-spot" within the bacterial chromosome. The only conventional remaining treatment options were the carbapenems. However, A. baumannii possesses an inherent class D β-lactamase gene (blaOXA-51-like) that can have the ability to confer carbapenem resistance. Additionally, mechanisms of carbapenem resistance have emerged that derive from the importation of the distantly related class D β-lactamase genes blaOXA-23 and blaOXA-58. Although not inducible, the expression of these genes is controlled by mobile promoters carried on ISAba elements. It has also been found that other resistance genes including the chromosomal class C β-lactamase genes conferring cephalosporin resistance are controlled in the same manner. Colistin is now considered to be the final drug capable of treating infections caused by carbapenem-resistant A. baumannii; however, strains are now being isolated that are resistant to this antibiotic as well. The increasing inability to treat infections caused by A. baumannii ensures that this pathogen more than ranks with MRSA or Clostridium difficile as a threat to modern medicine.201322894617
9929170.9999Global dissemination of beta-lactamases mediating resistance to cephalosporins and carbapenems. While the main era of beta-lactam discovery programs is over, these agents continue to be the most widely prescribed antimicrobials in both community and hospital settings. This has led to considerable beta-lactam pressure on pathogens, resulting in a literal explosion of new beta-lactamase variants of existing enzyme classes. Recent advances in the molecular tools used to detect and characterize beta-lactamases and their genes has, in part, fueled the large increase in communications identifying novel beta-lactamases, particularly in Gram-negative bacilli. It now seems clear that the beta-lactams themselves have shaped the field of new enzymes, and the evolution of key amino acid substitutions around the active sites of beta-lactamases continues to drive resistance. Over 130 variants of TEM beta-lactamase now exist, and more are reported in the scientific literature each month. The most disturbing current trend is that many bla structural genes normally limited to the chromosome are now mobilized on plasmids and integrons, broadening the spread of resistance to include carbapenems and cephamycins. Furthermore, in some Enterobacteriaceae, concomitant loss of outer membrane porins act in concert with these transmissible beta-lactamase genes to confer resistance to the most potent beta-lactams and inhibitor combinations available. Continued reviews of the literature are necessary in order to keep abreast of the ingenuity with which bacteria are changing the current genetic landscape to confer resistance to this important class of antimicrobials.200415482196
4871180.9999Colistin: from the shadows to a One Health approach for addressing antimicrobial resistance. Antimicrobial resistance (AMR) poses a serious threat to human, animal and environmental health worldwide. Colistin has regained importance as a last-resort treatment against multi-drug-resistant Gram-negative bacteria. However, colistin resistance has been reported in various Enterobacteriaceae species isolated from several sources. The 2015 discovery of the plasmid-mediated mcr-1 (mobile colistin resistance) gene conferring resistance to colistin was a major concern within the scientific community worldwide. The global spread of this plasmid - as well as the subsequent identification of 10 MCR-family genes and their variants that catalyse the addition of phosphoethanolamine to the phosphate group of lipid A - underscores the urgent need to regulate the use of colistin, particularly in animal production. This review traces the history of colistin resistance and mcr-like gene identification, and examines the impact of policy changes regarding the use of colistin on the prevalence of mcr-1-positive Escherichia coli and colistin-resistant E. coli from a One Health perspective. The withdrawal of colistin as a livestock growth promoter in several countries reduced the prevalence of colistin-resistant bacteria and its resistance determinants (e.g. mcr-1 gene) in farm animals, humans and the environment. This reduction was certainly favoured by the significant fitness cost associated with acquisition and expression of the mcr-1 gene in enterobacterial species. The success of this One Health intervention could be used to accelerate regulation of other important antimicrobials, especially those associated with bacterial resistance mechanisms linked to high fitness cost. The development of global collaborations and the implementation of sustainable solutions like the One Health approach are essential to manage AMR.202336640846
4864190.9999Colistin resistance mechanisms in Gram-negative bacteria: a Focus on Escherichia coli. Multidrug-resistant (MDR) Escherichia coli strains have rapidly increased worldwide, and effective antibiotic therapeutic options are becoming more restricted. As a polymyxin antibiotic, colistin has a long history of usage, and it is used as a final line of treatment for severe infections by Gram-negative bacteria (GNB) with high-level resistance. However, its application has been challenged by the emergence of E. coli colistin resistance. Hence, determining the mechanism that confers colistin resistance is crucial for monitoring and controlling the dissemination of colistin-resistant E. coli strains. This comprehensive review summarizes colistin resistance mechanisms in E. coli strains and concentrates on the history, mode of action, and therapeutic implications of colistin. We have mainly focused on the fundamental mechanisms of colistin resistance that are mediated by chromosomal or plasmid elements and discussed major mutations in the two-component systems (TCSs) genes and plasmids that transmit the mobilized colistin resistance resistant genes in E. coli strains.202336754367