Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins,cephalosporins,cephamycins,monobactams and carbapenems (ertapenem),although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure:a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis,the enzyme lactamase breaks the β-lactam ring open,deactivating the molecule's antibacterial properties.
Klebsiella pneumoniae is a Gram-negative,non-motile,encapsulated,lactose-fermenting,facultative anaerobic,rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.
Colistin,also known as polymyxin E,is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa,Klebsiella pneumoniae,or Acinetobacter. It comes in two forms:colistimethate sodium can be injected into a vein,injected into a muscle,or inhaled,and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug;it is produced by the reaction of colistin with formaldehyde and sodium bisulfite,which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives,as well as colistin. Resistance to colistin began to appear as of 2015.
Tigecycline,sold under the brand name Tygacil,is a tetracycline antibiotic medication for a number of bacterial infections. It is a glycylcycline administered intravenously. It was developed in response to the growing rate of antibiotic resistant bacteria such as Staphylococcus aureus,Acinetobacter baumannii,and E. coli. As a tetracycline derivative antibiotic,its structural modifications has expanded its therapeutic activity to include Gram-positive and Gram-negative organisms,including those of multi-drug resistance.
Pseudomonas aeruginosa is a common encapsulated,Gram-negative,aerobic–facultatively anaerobic,rod-shaped bacterium that can cause disease in plants and animals,including humans. A species of considerable medical importance,P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity,its intrinsically advanced antibiotic resistance mechanisms,and its association with serious illnesses –hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes.
Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins,carbapenems are members of the beta-lactam antibiotics drug class,which kill bacteria by binding to penicillin-binding proteins,thus inhibiting bacterial cell wall synthesis. However,these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore,carbapenems are typically unaffected by emerging antibiotic resistance,even to other beta-lactams.
Stenotrophomonas maltophilia is an aerobic,nonfermentative,Gram-negative bacterium. It is an uncommon bacterium and human infection is difficult to treat. Initially classified as Bacterium bookeri,then renamed Pseudomonas maltophilia,S. maltophilia was also grouped in the genus Xanthomonas before eventually becoming the type species of the genus Stenotrophomonas in 1993.
Acinetobacter baumannii is a typically short,almost round,rod-shaped (coccobacillus) Gram-negative bacterium. It is named after the bacteriologist Paul Baumann. It can be an opportunistic pathogen in humans,affecting people with compromised immune systems,and is becoming increasingly important as a hospital-derived (nosocomial) infection. While other species of the genus Acinetobacter are often found in soil samples,it is almost exclusively isolated from hospital environments. Although occasionally it has been found in environmental soil and water samples,its natural habitat is still not known.
Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics,the bacteria have beta-lactamase which degrade the beta-lactam rings,rendering the antibiotic ineffective. However,with beta-lactamase inhibitors,these enzymes on the bacteria are inhibited,thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own,they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.
NDM-1 is an enzyme that makes bacteria resistant to a broad range of beta-lactam antibiotics. These include the antibiotics of the carbapenem family,which are a mainstay for the treatment of antibiotic-resistant bacterial infections. The gene for NDM-1 is one member of a large gene family that encodes beta-lactamase enzymes called carbapenemases. Bacteria that produce carbapenemases are often referred to in the news media as "superbugs" because infections caused by them are difficult to treat. Such bacteria are usually sensitive only to polymyxins and tigecycline.
Plasmid-mediated resistance is the transfer of antibiotic resistance genes which are carried on plasmids. Plasmids possess mechanisms that ensure their independent replication as well as those that regulate their replication number and guarantee stable inheritance during cell division. By the conjugation process,they can stimulate lateral transfer between bacteria from various genera and kingdoms. Numerous plasmids contain addiction-inducing systems that are typically based on toxin-antitoxin factors and capable of killing daughter cells that don't inherit the plasmid during cell division. Plasmids often carry multiple antibiotic resistance genes,contributing to the spread of multidrug-resistance (MDR). Antibiotic resistance mediated by MDR plasmids severely limits the treatment options for the infections caused by Gram-negative bacteria,especially family Enterobacteriaceae. The global spread of MDR plasmids has been enhanced by selective pressure from antimicrobial medications used in medical facilities and when raising animals for food.
Carbapenem-resistant Enterobacteriaceae (CRE) or carbapenemase-producing Enterobacteriaceae (CPE) are Gram-negative bacteria that are resistant to the carbapenem class of antibiotics,considered the drugs of last resort for such infections. They are resistant because they produce an enzyme called a carbapenemase that disables the drug molecule. The resistance can vary from moderate to severe. Enterobacteriaceae are common commensals and infectious agents. Experts fear CRE as the new "superbug". The bacteria can kill up to half of patients who get bloodstream infections. Tom Frieden,former head of the Centers for Disease Control and Prevention has referred to CRE as "nightmare bacteria". Examples of enzymes found in certain types of CRE are KPC and NDM. KPC and NDM are enzymes that break down carbapenems and make them ineffective. Both of these enzymes,as well as the enzyme VIM have also been reported in Pseudomonas.
Avibactam is a non-β-lactam β-lactamase inhibitor developed by Actavis jointly with AstraZeneca. A new drug application for avibactam in combination with ceftazidime was approved by the FDA on February 25,2015,for treating complicated urinary tract (cUTI) and complicated intra-abdominal infections (cIAI) caused by antibiotic resistant-pathogens,including those caused by multi-drug resistant Gram-negative bacterial pathogens.
Gerard D. Wright,PhD,FRSC,is a professor in the Department of Biochemistry and Biomedical Sciences,and Canada Research Chair in Antibiotic Biochemistry at McMaster University who studies chemical compounds that can combat antibiotic resistance in bacteria. He is also an Associate member of the Departments of Chemistry and Chemical Biology and Pathology and Molecular Medicine. Wright was Chair of the Department of Biochemistry and Biomedical Sciences from 2001 to 2007. He was the Director of McMaster's Michael G. DeGroote Institute for Infectious Disease Research from 2007 to 2022. He is currently the executive director of Canada's Global Nexus for Pandemics and Biological Threats. He is also founding director of the McMaster Antimicrobial Research Centre,and co-founder of the McMaster High Throughput Screening Facility.
The mobilized colistin resistance (mcr) gene confers plasmid-mediated resistance to colistin,one of a number of last-resort antibiotics for treating Gram-negative infections. mcr-1,the original variant,is capable of horizontal transfer between different strains of a bacterial species. After discovery in November 2015 in E. coli from a pig in China it has been found in Escherichia coli,Salmonella enterica,Klebsiella pneumoniae,Enterobacter aerogenes,and Enterobacter cloacae. As of 2017,it has been detected in more than 30 countries on 5 continents in less than a year.
Kluyvera is a Gram negative,facultatively anaerobic bacterial and motile genus from the family of Enterobacteriaceae which have peritrichous flagella. Kluyvera occur in water,soil and sewage. Kluyvera bacteria can cause opportunistic infections in immunocompromised patients.
ESKAPE is an acronym comprising the scientific names of six highly virulent and antibiotic resistant bacterial pathogens including:Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa,and Enterobacter spp. The acronym is sometimes extended to ESKAPEE to include Escherichia coli. This group of Gram-positive and Gram-negative bacteria can evade or 'escape' commonly used antibiotics due to their increasing multi-drug resistance (MDR). As a result,throughout the world,they are the major cause of life-threatening nosocomial or hospital-acquired infections in immunocompromised and critically ill patients who are most at risk. P. aeruginosa and S. aureus are some of the most ubiquitous pathogens in biofilms found in healthcare. P. aeruginosa is a Gram-negative,rod-shaped bacterium,commonly found in the gut flora,soil,and water that can be spread directly or indirectly to patients in healthcare settings. The pathogen can also be spread in other locations through contamination,including surfaces,equipment,and hands. The opportunistic pathogen can cause hospitalized patients to have infections in the lungs,blood,urinary tract,and in other body regions after surgery. S. aureus is a Gram-positive,cocci-shaped bacterium,residing in the environment and on the skin and nose of many healthy individuals. The bacterium can cause skin and bone infections,pneumonia,and other types of potentially serious infections if it enters the body. S. aureus has also gained resistance to many antibiotic treatments,making healing difficult. Because of natural and unnatural selective pressures and factors,antibiotic resistance in bacteria usually emerges through genetic mutation or acquires antibiotic-resistant genes (ARGs) through horizontal gene transfer - a genetic exchange process by which antibiotic resistance can spread.
Asad Ullah Khan is an Indian microbiologist,biochemist and a professor at the Interdisciplinary Biotechnology Unit of the Aligarh Muslim University. He is known for his studies on multidrug resistant clinical strains as well as for the first sighting in India of Aligarh super bug (NDM-4),a variant of New Delhi metallo-beta-lactamase 1 (NDM-1). He is an elected fellow of the Royal Society of Chemistry,the Biotech Research Society,India and the Indian Academy of Microbiological Sciences. The Department of Biotechnology of the Government of India awarded him the National Bioscience Award for Career Development,one of the highest Indian science awards,for his contributions to biosciences,in 2012.
Mustard is a database that tracks Antimicrobial Resistance Determinants (ARDs). The method by which it tracks ARDs is using their own method adapted from Protein Homology Modelling called Pairwise Comparative Modelling (PCM),which increase specificity protein prediction,especially for distantly related protein homologues. Using PCM,6095 ARDs from 20 families in the human gut microbiota. Antibiotic resistance databases used were ResFinder,ARG-ANNOT,the now defunct Lahey Clinic,Marilyn Roberts website for tetracycline and macrolide resistance genes and metagenomics.
Lipid A phosphoethanolamine transferase is an enzyme that modifies Lipid A by linkage to a phosphoethanolamine moiety. Doing so at some positions reduces the affinity to colistin and related polymyxins,resulting in reduced activity of the antimicrobial. This type of resistance is known as target modification. This type of enzyme is of special medical note,as it offers resistance to a last-resort antibiotic. The modifications also provide cross-resistance to host immunity factors,specifically antimicrobial peptides and lysozyme. EC 2.7.8.43 catalyzes one of the following three reactions:
