Karen Bush | |
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Alma mater | University of California (Santa Barbara) post-doctoral fellow; Indiana University Bloomington, Ph.D, 1970; Monmouth College , B.A., 1965 |
Known for | Antimicrobial resistance research, Beta-lactam antibiotics |
Spouse(s) | Daniel J. Watts, (m.) 1973 - present |
Children | (2) Edward J. Watts and Amber E. Watts |
Awards | Excellence in Standards Award (2015), Hamao Umezawa Memorial Award (2017) |
Website | https://biology.indiana.edu/about/faculty/emeriti/bush-karen.html |
Karen Bush is an American biochemist. She is a professor of Practice in Biology Emerita at Indiana University Bloomington and served as the interim director of the Biotechnology program from 2019-2022. Bush conducts research focusing on the activity of novel antimicrobial agents against Gram-negative bacteria and bacterial resistance mechanisms to beta-lactam antibiotics. [1]
Bush received her BA, magna cum laude from Monmouth College in 1965, with a major in chemistry and a minor in math-physics. In 1970 Bush graduated from Indiana University Bloomington with her Ph.D. in biochemistry under Henry R. Mahler. [2] [3] Bush was a postdoctoral fellow at the University of California, Santa Barbara from 1970 to 1971. [1]
Bush is internationally known for her research on the discovery and characterization of beta-lactamases, the family of enzymes that confer resistance to penicillins and cephalosporins. Antibiotic resistance has emerged as a key threat to the global fight against infectious diseases, and Bush's research into the mechanisms of action for beta-lactamases has provided key insights in development of beta-lactamase inhibitors to combat these modes of resistance. Her review article on beta-lactamases established commonly used nomenclature. [4] She co-curated a website for this family of enzymes that has named over 2000 beta lactamases. [5]
During her 36 years of antibiotic discovery efforts in the pharmaceutical industry, Bush worked on the research teams that brought 9 anti-infective leads to clinical trials and 5 antibiotics to FDA and/or EMA approval (aztreonam, piperacillin-tazobactam, levofloxacin, doripenem and ceftobiprole). As a professor, Bush has continued to lead research characterizing beta-lactam resistance in enteric bacteria and collaborated with pharmaceutical companies in evaluating clinical potential of novel antibacterial agents by studying the spectrum of activity and mechanisms of resistance. This work has been included in data packages submitted to the FDA for drug approval, and research from her laboratory has supported the approval process for 6 new antibacterial therapies (ceftolozane-tazobactam, ceftazidime-avibactam, plazomicin, eravacycline, imipenem-relebactam and cefiderocol).
After completing her postdoctoral research, Bush became an instructor of biochemistry in the University of North Carolina Chapel Hill School of Medicine for a year before serving as an visiting assistant professor of chemistry at the University of Delaware from 1972 to 1973. She then started an 18-year stint at The Squibb Institute for Medical Research in Princeton, NJ, spending her first 3 years in the analytical chemistry department before beginning her research on beta-lactamases and beta-lactamase inhibitors. While at The Squibb Institute, Bush was part of the team that discovered Aztreonam and rose from a Research Investigator position to increasing leadership and research scientist roles, ultimately named not only a principal investigator but also as a research leader and a research fellow. [1]
She then went on to American Cyanamid/American Home Products/Wyeth-Ayerst in Pearl River, NJ. Continuing her research and discovery efforts in antibiotic chemotherapy where she led teams that discovered a new carbapenem and supported the registration and launch of piperacillin-tazobactam (Zosyn®). After a year as Director of Microbial Biochemistry at the Astra Research Center in Boston, Bush moved on to lead antibacterial discovery and development teams at Johnson & Johnson Pharmaceutical Research & Development, Raritan NJ from 1997 to 2009 when she became an independent consultant to a number of pharmaceutical and biotechnology companies. [3]
In 2010, Bush returned to academia, to lead research studies, to teach and mentor graduate students, and recently retired as a professor of Practice in Biotechnology in the Biology Department at Indiana University in Bloomington, Indiana.
Within the American Society of Microbiology, she was elected a Fellow of the American Academy of Microbiology in 2000 [6] and selected as the ICAAC Lecturer in 2014.
In 2015 she was awarded the "Excellence in Standards Award" from the Clinical and Laboratory Standards Institute (CLSI). [6] In 2015 she was also recognized with the Monmouth College Hall of Achievement Award.
In recognition of her outstanding research in antibiotic chemotherapy, Bush received the Hamao Umezawa Memorial Award on November 24, 2017, at the 30th annual meeting for the International Society of Chemotherapy for Infection and Cancer, held in Taipei, Taiwan. [7] She was the first woman to receive the award. [3]
As a world recognized expert in the field of antibiotic discovery, Bush is involved in numerous scientific communities and services.
Bush has authored over 225 peer-reviewed publications with over 30,000 citations and an overall h-index of 86. [12] She has co-authored 25 book chapters, edited a book, authored or co-authored over 235 poster presentations at international meetings, and has been an invited speaker at over 120 scientific meetings or symposia. She is an inventor on 4 issued US patents. [13]
Representative publications include:
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.
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, resistance has evolved. Antimicrobial resistance and antineoplastic resistance challenge clinical care and drive research. When an organism is resistant to more than one drug, it is said to be multidrug-resistant.
Sir Richard Brook Sykes is a British microbiologist, the chair of the Royal Institution, the UK Stem Cell Foundation, and the trustees at King Edward VII's Hospital, and chancellor of Brunel University. As of June 2021, he is chair of the UK's Vaccine Taskforce, where he is responsible for overseeing the delivery of the COVID-19 vaccination programme, including preparations for booster programmes and encouraging vaccine innovation in the UK.
The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as Cephalosporium.
Cephems are a sub-group of β-lactam antibiotics including cephalosporins and cephamycins. It is one of the most common 4-membered ring heterocycle. Produced by actinomycetes, cephamycins were found to display antibacterial activity against a wide range of bacteria, including those resistant to penicillin and cephalosporins. The antimicrobial properties of Cephem include the attachment to certain penicillin-binding proteins that are involved in the production of cell walls of bacteria.
Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".
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.
Sulbactam is a β-lactamase inhibitor. This drug is given in combination with β-lactam antibiotics to inhibit β-lactamase, an enzyme produced by bacteria that destroys the antibiotics.
Faropenem is an orally active beta-lactam antibiotic belonging to the penem group. It is resistant to some forms of extended-spectrum beta-lactamase. It is available for oral use.
Streptomyces clavuligerus is a species of Gram-positive bacterium notable for producing clavulanic acid.
Monobactams are bacterially-produced monocyclic β-lactam antibiotics. The β-lactam ring is not fused to another ring, in contrast to most other β-lactams.
Thienamycin is one of the most potent naturally produced antibiotics known thus far, discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes. Thienamycin is a zwitterion at pH 7.
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.
ESCAPPM or ESCHAAPPM is a mnemonic for the organisms with inducible beta-lactamase activity that is chromosomally mediated.
Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.
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.
Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a fixed-dose combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.
Ceftazidime/avibactam, sold under the brand name Avycaz among others, is a fixed-dose combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a β-lactamase inhibitor. It is used to treat complicated intra-abdominal infections, urinary tract infections, and pneumonia. It is only recommended when other options are not appropriate. It is given by infusion into a vein.
Lynn L. Silver is an American born scientist best known for her contributions to the field of antibacterial discovery and development. With over 30 years of experience in the antibacterial discovery field and over 70 peer reviewed publications, Silver provides insight and advice to the research community on global advisory panels, international collaborations for addressing antibiotic resistance issues. Silver has published several highly cited reviews in the field of antibacterial discovery.
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.