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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.
Mutagenesis is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures. A mutagen is a mutation-causing agent, be it chemical or physical, which results in an increased rate of mutations in an organism's genetic code. In nature mutagenesis can lead to cancer and various heritable diseases, and it is also a driving force of evolution. Mutagenesis as a science was developed based on work done by Hermann Muller, Charlotte Auerbach and J. M. Robson in the first half of the 20th century.
Site-directed mutagenesis is a molecular biology method that is used to make specific and intentional mutating changes to the DNA sequence of a gene and any gene products. Also called site-specific mutagenesis or oligonucleotide-directed mutagenesis, it is used for investigating the structure and biological activity of DNA, RNA, and protein molecules, and for protein engineering.
The SOS response is a global response to DNA damage in which the cell cycle is arrested and DNA repair and mutagenesis are induced. The system involves the RecA protein. The RecA protein, stimulated by single-stranded DNA, is involved in the inactivation of the repressor (LexA) of SOS response genes thereby inducing the response. It is an error-prone repair system that contributes significantly to DNA changes observed in a wide range of species.
In genetics, the mutation rate is the frequency of new mutations in a single gene, nucleotide sequence, or organism over time. Mutation rates are not constant and are not limited to a single type of mutation; there are many different types of mutations. Mutation rates are given for specific classes of mutations. Point mutations are a class of mutations which are changes to a single base. Missense, nonsense, and synonymous mutations are three subtypes of point mutations. The rate of these types of substitutions can be further subdivided into a mutation spectrum which describes the influence of the genetic context on the mutation rate.
Fosmidomycin is an antibiotic that was originally isolated from culture broths of bacteria of the genus Streptomyces. It specifically inhibits DXP reductoisomerase, a key enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. It is a structural analogue of 2-C-methyl-D-erythrose 4-phosphate. It inhibits the E. coli enzyme with a KI value of 38 nM (4), MTB at 80 nM, and the Francisella enzyme at 99 nM. Several mutations in the E. coli DXP reductoisomerase were found to confer resistance to fosmidomycin.
The rpoB gene encodes the β subunit of bacterial RNA polymerase and the homologous plastid-encoded RNA polymerase (PEP). It codes for 1342 amino acids in E. coli, making it the second-largest polypeptide in the bacterial cell. It is targeted by the rifamycin family of antibacterials, such as rifampin. Mutations in rpoB that confer resistance to rifamycins do so by altering the protein's drug-binding residues, thereby reducing affinity for these antibiotics.
Enoxacin is an oral broad-spectrum fluoroquinolone antibacterial agent used in the treatment of urinary tract infections and gonorrhea. Insomnia is a common adverse effect. It is no longer available in the United States.
An efflux pump is an active transporter in cells that moves out unwanted material. Efflux pumps are an important component in bacteria in their ability to remove antibiotics. The efflux could also be the movement of heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals, bacterial metabolites and neurotransmitters. All microorganisms, with a few exceptions, have highly conserved DNA sequences in their genome that encode efflux pumps. Efflux pumps actively move substances out of a microorganism, in a process known as active efflux, which is a vital part of xenobiotic metabolism. This active efflux mechanism is responsible for various types of resistance to bacterial pathogens within bacterial species - the most concerning being antibiotic resistance because microorganisms can have adapted efflux pumps to divert toxins out of the cytoplasm and into extracellular media.
Sulfamethizole is a sulfonamide antibiotic.
Hygromycin B is an antibiotic produced by the bacterium Streptomyces hygroscopicus. It is an aminoglycoside that kills bacteria, fungi and other eukaryotic cells by inhibiting protein synthesis.
Evelyn M. Witkin was an American bacterial geneticist at Cold Spring Harbor Laboratory (1944–1955), SUNY Downstate Medical Center (1955–1971), and Rutgers University (1971–1991). Witkin was considered innovative and inspirational as a scientist, teacher and mentor.
Fleroxacin is a quinolone antibiotic. It is sold under the brand names Quinodis and Megalocin.
Mecillinam (INN) or amdinocillin (USAN) is an extended-spectrum penicillin antibiotic of the amidinopenicillin class that binds specifically to penicillin binding protein 2 (PBP2), and is only considered to be active against Gram-negative bacteria. It is used primarily in the treatment of urinary tract infections, and has also been used to treat typhoid and paratyphoid fever. Because mecillinam has very low oral bioavailability, an orally active prodrug was developed: pivmecillinam.
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.
DNA polymerase IV is a prokaryotic polymerase that is involved in mutagenesis and is encoded by the dinB gene. It exhibits no 3′→5′ exonuclease (proofreading) activity and hence is error prone. In E. coli, DNA polymerase IV is involved in non-targeted mutagenesis. Pol IV is a Family Y polymerase expressed by the dinB gene that is switched on via SOS induction caused by stalled polymerases at the replication fork. During SOS induction, Pol IV production is increased tenfold and one of the functions during this time is to interfere with Pol III holoenzyme processivity. This creates a checkpoint, stops replication, and allows time to repair DNA lesions via the appropriate repair pathway. Another function of Pol IV is to perform translesion synthesis at the stalled replication fork like, for example, bypassing N2-deoxyguanine adducts at a faster rate than transversing undamaged DNA. Cells lacking dinB gene have a higher rate of mutagenesis caused by DNA damaging agents.
Nemonoxacin is a non-fluorinated quinolone antibiotic undergoing clinical trials. It has the same mechanism of action as fluouroquinolones; it inhibits DNA gyrase, preventing DNA synthesis, gene duplication, and cell division. At the end of 2016, it had reached market in Taiwan, Russia, the Commonwealth Independent States, Turkey, mainland China, and Latin America under the brand name Taigexyn. Nemonoxacin has completed phase 2 trials in the US and has moved on to phase 3 trials. The U.S. Food and Drug Administration (FDA) has granted nemonoxacin qualified infectious disease product (QIDP) and fast track designations for community-acquired bacterial pneumonia (CAP) and acute bacterial skin and skin-structure infections (ABSSSI).
Abraham Eisenstark was an American professor of microbiology. He was a Guggenheim Fellow for the academic year 1958–1959.
Karen Joy Shaw is an American microbiologist and discoverer of novel antifungal and antibacterial compounds. She is best known for her work on aminoglycoside resistance in bacteria as well as leading drug discovery research teams. As Senior Vice President of Biology at Trius Therapeutics, Inc. her work was critical to the development of the oxazolidinone antibiotic tedizolid phosphate (Sivextro) as well as the discovery of the TriBE inhibitors, a novel class of DNA gyrase/Topoisomerase IV antibacterial agents that target both Gram-positive and Gram-negative organisms.[2] As Chief Scientific Officer at Amplyx Pharmaceuticals, Shaw was responsible for the preclinical development of the novel antifungal fosmanogepix, a first-in-class broad-spectrum antifungal prodrug that is currently in Phase 2 clinical development for the treatment of invasive fungal infections. She also discovered APX2039, a unique Gwt1 inhibitor that is in preclinical development for the treatment of cryptococcal meningitis.
A. C. Matin was a Pakistani-American microbiologist, immunologist, academician and researcher. He was a professor of microbiology and immunology at Stanford University School of Medicine.
References
- ↑ Miller, Jeffrey H. (2013-04-01). "My long and winding road to mutagenesis and DNA repair pathways". DNA Repair. 12 (4): 247–256. doi:10.1016/j.dnarep.2013.01.005. PMID 23620876.
- ↑ Song, Lisa Yun; D'Souza, Sara; Lam, Karen; Kang, Tina Manzhu; Yeh, Pamela; Miller, Jeffrey H. (2016-03-25). "Erratum for Song et al., Exploring Synergy between Classic Mutagens and Antibiotics To Examine Mechanisms of Synergy and Antibiotic Action". Antimicrobial Agents and Chemotherapy. 60 (4): 2600. doi:10.1128/AAC.00429-16. ISSN 0066-4804. PMC 4808235 . PMID 27016560.
- ↑ "Jeffery H Miller PhD | Microbiology Immunology & Molecular Genetics". mimg.ucla.edu. 2023-11-09. Retrieved 2024-10-05.
- ↑ Baba, Tomoya; Ara, Takeshi; Hasegawa, Miki; Takai, Yuki; Okumura, Yoshiko; Baba, Miki; Datsenko, Kirill A; Tomita, Masaru; Wanner, Barry L; Mori, Hirotada (Feb 21, 2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection". Molecular Systems Biology. 2 (1). doi:10.1038/msb4100050. ISSN 1744-4292. PMC 1681482 . PMID 16738554.