DOCSLIB.ORG

Antibiotic Adjuvants Â

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antibiotic Adjuvants  Bioorganic & Medicinal Chemistry Letters 27 (2017) 4221–4228 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Digest Antibiotic adjuvants – A strategy to unlock bacterial resistance to antibiotics Concepción González-Bello Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela, Jenaro de la Fuente s/n, 15782 Santiago de Compostela, Spain article info abstract Article history: Resistance to available antibiotics in pathogenic bacteria is currently a global challenge since the number Received 23 June 2017 of strains that are resistant to multiple types of antibiotics has increased dramatically each year and has Revised 8 August 2017 spread worldwide. To unlock this problem, the use of an ‘antibiotic adjuvant’ in combination with an Accepted 13 August 2017 antibiotic is now being exploited. This approach enables us to prolong the lifespan of these life-saving Available online 14 August 2017 drugs. This digests review provides an overview of the main types of antibiotic adjuvants, the basis of their operation and the remaining issues to be tackled in this field. Particular emphasis is placed on those Keywords: compounds that are already in clinical development, namely b-lactamase inhibitors. Resistance breakers Ó 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND Antibiotic potentiators ESKAPE pathogens license (http://creativecommons.org/licenses/by-nc-nd/4.0/). b-Lactamase inhibitors Efflux pump inhibitors Permeabilizers The discovery of penicillin during the first half of the 20th cen- Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Provi- tury and all the antibiotics developed thereafter undoubtedly rep- dencia spp., and Morganella spp.). These bacteria are resistant to resents one of the most important achievements in medicine. carbapenems, which are the only remaining therapy that is often These drugs have not only saved millions of lives but are also a considered as antibiotics of last resort.4 To this list we must add key tool in the success of common hospital procedures such as Mycobacterium tuberculosis, the causative agent of tuberculosis, general surgery, organ transplantation, dialysis for renal failure which is already considered as a top global health priority. The and chemotherapy for cancer, for which their capacity to treat sec- high and medium categories involve increasingly drug-resistant ondary infections is crucial. Regrettably, the ability of these drugs bacteria that require more monitoring and prevention activities. to cure infectious diseases is now in serious danger due to the This priority list of bacterial pathogens is an excellent guide for emergence and spread worldwide of strains that are multidrug- the prioritization of incentives and funding for R&D aimed at dis- resistant to antibiotics.1 The European Center for Disease Preven- covering new and effective antibacterial therapies, which is tion and Control (ECDC) estimates that about 25,000 Europeans undoubtedly necessary.5 die each year as a direct consequence of a multidrug-resistant A recent study has shown that resistance to antibiotics is a nat- infection and €1.5 billion is spent in extra patient care costs.2 ural phenomenon that predates the golden age of antibiotic ther- According to the U.S. Center for Disease Control & Prevention apy due to the intrinsic evolutionary character and adaptability (CDC), a similar number of deaths also occur in the USA. of bacteria.6 Nonetheless, human behavior has undoubtedly been The WHO has recently published a global priority pathogens list decisive in reaching bacterial resistance to the current alarming of antibiotic-resistant bacteria (Table 1).3 Based on diverse criteria levels. One of the key factors is the abuse and misuse of these drugs such as mortality, prevalence of resistance, treatability or current over the years in humans, animals and plants, including for the pipeline, bacterial pathogens have been ranked as critical, high treatment of non-bacterial diseases. As shown recently, this behav- and medium. This study revealed that the situation is highly criti- ior has favored the appearance of tolerance and this, in turn, facil- cal for healthcare-associated infections caused by the Gram-nega- itates the emergence of resistance.7 Another critical point that is tive ESKAPE pathogens Acinetobacter baumannii, Pseudomonas limiting our capacity to deal with multidrug resistant bacteria is aeruginosa and Enterobacteriaceae (including Klebsiella pneumoniae, the flagging investment in R&D on novel antibiotics by the large pharmaceutical companies since the 1960s. This is mainly due E-mail address: [email protected] to: (a) the huge economic cost of bringing a drug to the market; http://dx.doi.org/10.1016/j.bmcl.2017.08.027 0960-894X/Ó 2017 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 4222 C. González-Bello / Bioorganic & Medicinal Chemistry Letters 27 (2017) 4221–4228 Table 1 WHO priority bacterial pathogens list for research and development of new antibiotics.a Priority Bacterial Pathogen Critical Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae,b carbapenem-resistant, 3rd generation cephalosporin-resistant Mycobacteria, including Mycobacterium tuberculosis High Enterococcus faecium, vancomycin-resistant Staphylococcus aureus, methicillin-resistant, vancomycin intermediate and resistant Helicobacter pylori, clarithromycin-resistant Campylobacter, fluoroquinolone-resistant Salmonella spp., fluoroquinolone-resistant Neisseria gonorrhoeae, 3rd generation cephalosporin-resistant, fluoroquinolone-resistant Medium Streptococcus pneumoniae, penicillin-non-susceptible Haemophilus influenza, ampicillin-resistant Shigella spp., fluoroquinolone-resistant Fig. 1. Antibiotics in clinical trials that have a new mechanism of action. a Ref. 3. b It includes Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., and Providencia spp., Morganella spp. Taken together, it seems clear that it is crucial to search not only for more effective anti-infective drugs but also to develop novel chemical entities with new mechanisms of action. A great deal of (b) the low profit margin for non-chronic diseases of this type com- effort is currently being devoted, particularly in academia, to inves- pared with continuing ones such as cancer or mental diseases and tigate the potential of unexploited essential processes in bacteria (c) the belief that the great therapeutic arsenal available was suffi- and to develop novel scaffolds that target them, as well as to study cient to deal with this issue.8 As a consequence, the clinical pipe- the biochemical basis of these targets in detail. The increasing line for antibiotics is almost empty compared to more than 500 availability of bacterial genome sequences in general, and the iden- chronic-disease drugs for which resistance is not an issue. tification of the essential genes for bacterial survival in particular, It is also relevant that most of the antibiotics in clinical use tar- have contributed greatly to the progress made in this area of get a small number and the same type of key functions for bacterial research. However, the development of antibiotics that act on survival and resistance to them is widespread and well known novel targets is a very challenging and expensive task, as evidenced (Table 2).9 by the fact that there are only two compounds in clinical trials that Specifically, the available antibiotics target: (1) cell-wall meet this premise. A good example is CARB-X (Combating Antibi- biosynthesis; (2) protein synthesis (subunit 30S or 50S of ribo- otic Resistant Bacteria Biopharmaceutical Accelerator), the world’s some); (3) DNA replication and repair (RNA polymerase, DNA gyr- largest public-private partnership, which was recently created and ase); (4) folic acid metabolism; and (5) membrane structure. An is devoted antibacterial preclinical R&D.11 Funded by BARDA and analysis of the antibiotics currently in clinical development (about the UK’s Wellcome Trust, and supported by NIAID, CARB-X will 40 small molecules) revealed that unfortunately this trend has not spend $450 million from 2017À2021 to bring innovative treat- changed significantly (Fig. S1).10 The Pew Charitable Trust high- ments toward clinical trials. In contrast, greater success has been lighted that nearly all of the antibiotics approved in the last achieved with those approaches that minimize the emergence 30 years are modifications of earlier classes to make them more and impact of resistance to antibiotics by the use of an ‘antibiotic efficient and robust against resistant bacteria. Specifically, only adjuvant’ in combination with an antibiotic. This booming and suc- two of them are compounds with a new mechanism of action cessful strategy will be the focus of this digest review. An overview (Fig. 1): (a) Brilacidin (PMX-30063, Phase 2, Cellceutix Corp.) is a of the recent efforts carried out on such combined therapies to face synthetic mimetic of host defense protein, which is the first line the challenge of multidrug resistance to antibiotics is reviewed. of defense against microbial infection in many species; and (b) Antibiotic Adjuvants: These
Load more

Recommended publications
  • WO 2015/179249 Al 26 November 2015 (26.11.2015) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/179249 Al 26 November 2015 (26.11.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/11 (2006.01) A61K 38/08 (2006.01) kind of national protection available): AE, AG, AL, AM, C12N 15/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2015/031213 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 15 May 2015 (15.05.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/000,43 1 19 May 2014 (19.05.2014) US kind of regional protection available): ARIPO (BW, GH, 62/129,746 6 March 2015 (06.03.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (72) Inventors; and TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicants : GELLER, Bruce, L.
    [Show full text]
  • Brilacidin First-In-Class Defensin-Mimetic Drug Candidate
    Brilacidin First-in-Class Defensin-Mimetic Drug Candidate Mechanism of Action, Pre/Clinical Data and Academic Literature Supporting the Development of Brilacidin as a Potential Novel Coronavirus (COVID-19) Treatment April 20, 2020 Page # I. Brilacidin: Background Information 2 II. Brilacidin: Two Primary Mechanisms of Action 3 Membrane Disruption 4 Immunomodulatory 7 III. Brilacidin: Several Complementary Ways of Targeting COVID-19 10 Antiviral (anti-SARS-CoV-2 activity) 11 Immuno/Anti-Inflammatory 13 Antimicrobial 16 IV. Brilacidin: COVID-19 Clinical Development Pathways 18 Drug 18 Vaccine 20 Next Steps 24 V. Brilacidin: Phase 2 Clinical Trial Data in Other Indications 25 VI. AMPs/Defensins (Mimetics): Antiviral Properties 30 VII. AMPs/Defensins (Mimetics): Anti-Coronavirus Potential 33 VIII. The Broader Context: Characteristics of the COVID-19 Pandemic 36 Innovation Pharmaceuticals 301 Edgewater Place, Ste 100 Wakefield, MA 01880 978.921.4125 [email protected] Innovation Pharmaceuticals: Mechanism of Action, Pre/Clinical Data and Academic Literature Supporting the Development of Brilacidin as a Potential Novel Coronavirus (COVID-19) Treatment (April 20, 2020) Page 1 of 45 I. Brilacidin: Background Information Brilacidin (PMX-30063) is Innovation Pharmaceutical’s lead Host Defense Protein (HDP)/Defensin-Mimetic drug candidate targeting SARS-CoV-2, the virus responsible for COVID-19. Laboratory testing conducted at a U.S.-based Regional Biocontainment Laboratory (RBL) supports Brilacidin’s antiviral activity in directly inhibiting SARS-CoV-2 in cell-based assays. Additional pre-clinical and clinical data support Brilacidin’s therapeutic potential to inhibit the production of IL-6, IL-1, TNF- and other pro-inflammatory cytokines and chemokines (e.g., MCP-1), identified as central drivers in the worsening prognoses of COVID-19 patients.
    [Show full text]
  • Current Topics in Medicinal Chemistry, 2017, 17, 576-589
    576 Send Orders for Reprints to [email protected] Current Topics in Medicinal Chemistry, 2017, 17, 576-589 REVIEW ARTICLE ISSN: 1568-0266 eISSN: 1873-5294 Impact Factor: Mimics of Host Defense Proteins; Strategies for Translation to Therapeutic 2.9 The international journal for in-depth reviews on Applications Current Topics in Medicinal Chemistry BENTHAM SCIENCE Richard W. Scott*,1 and Gregory N. Tew2 1Fox Chase Chemical Diversity Center, Pennsylvania Biotechnology Center, Doylestown, PA, USA; 2Polymer Science and Engineering, Veterinary and Animal Science, Cell and Molecular Biology, University of Massachusetts, Amherst MA, USA Abstract: New infection treatments are urgently needed to combat the rising threat of multi-drug re- sistant bacteria. Despite early clinical set-backs attention has re-focused on host defense proteins (HDPs), as potential sources for new and effective antimicrobial treatments. HDPs appear to act at multiple targets and their repertoire includes disruptive membrane and intracellular activities against numerous types of pathogens as well as immune modulatory functions in the host. Importantly, these novel activities are associated with a low potential for emergence of resistance and little cross- resistance with other antimicrobial agents. Based on these properties, HDPs appear to be ideal candi- A R T I C L E H I S T O R Y dates for new antibiotics; however, their development has been plagued by the many therapeutic limi- tations associated with natural peptidic agents. This review focuses on HDP mimetic approaches Received: May 22, 2015 Revised: October 29, 2015 aimed to improve metabolic stability, pharmacokinetics, safety and manufacturing processes. Early ef- Accepted: November 30, 2015 forts with β-peptide or peptoid analogs focused on recreating stable facially amphiphilic structures but DOI: 10.2174/15680266166661607 demonstrated that antimicrobial activity was modulated by more, complex structural properties.
    [Show full text]
  • B-Lactams: Chemical Structure, Mode of Action and Mechanisms of Resistance
    b-Lactams: chemical structure, mode of action and mechanisms of resistance Ru´ben Fernandes, Paula Amador and Cristina Prudeˆncio This synopsis summarizes the key chemical and bacteriological characteristics of b-lactams, penicillins, cephalosporins, carbanpenems, monobactams and others. Particular notice is given to first-generation to fifth-generation cephalosporins. This review also summarizes the main resistance mechanism to antibiotics, focusing particular attention to those conferring resistance to broad-spectrum cephalosporins by means of production of emerging cephalosporinases (extended-spectrum b-lactamases and AmpC b-lactamases), target alteration (penicillin-binding proteins from methicillin-resistant Staphylococcus aureus) and membrane transporters that pump b-lactams out of the bacterial cell. Keywords: b-lactams, chemical structure, mechanisms of resistance, mode of action Historical perspective Alexander Fleming first noticed the antibacterial nature of penicillin in 1928. When working with Antimicrobials must be understood as any kind of agent another bacteriological problem, Fleming observed with inhibitory or killing properties to a microorganism. a contaminated culture of Staphylococcus aureus with Antibiotic is a more restrictive term, which implies the the mold Penicillium notatum. Fleming remarkably saw natural source of the antimicrobial agent. Similarly, under- the potential of this unfortunate event. He dis- lying the term chemotherapeutic is the artificial origin of continued the work that he was dealing with and was an antimicrobial agent by chemical synthesis [1]. Initially, able to describe the compound around the mold antibiotics were considered as small molecular weight and isolates it. He named it penicillin and published organic molecules or metabolites used in response of his findings along with some applications of penicillin some microorganisms against others that inhabit the same [4].
    [Show full text]
  • Penicillin Allergy Guidance Document
    Penicillin Allergy Guidance Document Key Points Background Careful evaluation of antibiotic allergy and prior tolerance history is essential to providing optimal treatment The true incidence of penicillin hypersensitivity amongst patients in the United States is less than 1% Alterations in antibiotic prescribing due to reported penicillin allergy has been shown to result in higher costs, increased risk of antibiotic resistance, and worse patient outcomes Cross-reactivity between truly penicillin allergic patients and later generation cephalosporins and/or carbapenems is rare Evaluation of Penicillin Allergy Obtain a detailed history of allergic reaction Classify the type and severity of the reaction paying particular attention to any IgE-mediated reactions (e.g., anaphylaxis, hives, angioedema, etc.) (Table 1) Evaluate prior tolerance of beta-lactam antibiotics utilizing patient interview or the electronic medical record Recommendations for Challenging Penicillin Allergic Patients See Figure 1 Follow-Up Document tolerance or intolerance in the patient’s allergy history Consider referring to allergy clinic for skin testing Created July 2017 by Macey Wolfe, PharmD; John Schoen, PharmD, BCPS; Scott Bergman, PharmD, BCPS; Sara May, MD; and Trevor Van Schooneveld, MD, FACP Disclaimer: This resource is intended for non-commercial educational and quality improvement purposes. Outside entities may utilize for these purposes, but must acknowledge the source. The guidance is intended to assist practitioners in managing a clinical situation but is not mandatory. The interprofessional group of authors have made considerable efforts to ensure the information upon which they are based is accurate and up to date. Any treatments have some inherent risk. Recommendations are meant to improve quality of patient care yet should not replace clinical judgment.
    [Show full text]
  • Computational Antibiotics Book
    Andrew V DeLong, Jared C Harris, Brittany S Larcart, Chandler B Massey, Chelsie D Northcutt, Somuayiro N Nwokike, Oscar A Otieno, Harsh M Patel, Mehulkumar P Patel, Pratik Pravin Patel, Eugene I Rowell, Brandon M Rush, Marc-Edwin G Saint-Louis, Amy M Vardeman, Felicia N Woods, Giso Abadi, Thomas J. Manning Computational Antibiotics Valdosta State University is located in South Georgia. Computational Antibiotics Index • Computational Details and Website Access (p. 8) • Acknowledgements (p. 9) • Dedications (p. 11) • Antibiotic Historical Introduction (p. 13) Introduction to Antibiotic groups • Penicillin’s (p. 21) • Carbapenems (p. 22) • Oxazolidines (p. 23) • Rifamycin (p. 24) • Lincosamides (p. 25) • Quinolones (p. 26) • Polypeptides antibiotics (p. 27) • Glycopeptide Antibiotics (p. 28) • Sulfonamides (p. 29) • Lipoglycopeptides (p. 30) • First Generation Cephalosporins (p. 31) • Cephalosporin Third Generation (p. 32) • Fourth-Generation Cephalosporins (p. 33) • Fifth Generation Cephalosporin’s (p. 34) • Tetracycline antibiotics (p. 35) Computational Antibiotics Antibiotics Covered (in alphabetical order) Amikacin (p. 36) Cefempidone (p. 98) Ceftizoxime (p. 159) Amoxicillin (p. 38) Cefepime (p. 100) Ceftobiprole (p. 161) Ampicillin (p. 40) Cefetamet (p. 102) Ceftoxide (p. 163) Arsphenamine (p. 42) Cefetrizole (p. 104) Ceftriaxone (p. 165) Azithromycin (p.44) Cefivitril (p. 106) Cefuracetime (p. 167) Aziocillin (p. 46) Cefixime (p. 108) Cefuroxime (p. 169) Aztreonam (p.48) Cefmatilen ( p. 110) Cefuzonam (p. 171) Bacampicillin (p. 50) Cefmetazole (p. 112) Cefalexin (p. 173) Bacitracin (p. 52) Cefodizime (p. 114) Chloramphenicol (p.175) Balofloxacin (p. 54) Cefonicid (p. 116) Cilastatin (p. 177) Carbenicillin (p. 56) Cefoperazone (p. 118) Ciprofloxacin (p. 179) Cefacetrile (p. 58) Cefoselis (p. 120) Clarithromycin (p. 181) Cefaclor (p.
    [Show full text]
  • Management of Penicillin and Beta-Lactam Allergy
    Management of Penicillin and Beta-Lactam Allergy (NB Provincial Health Authorities Anti-Infective Stewardship Committee, September 2017) Key Points • Beta-lactams are generally safe; allergic and adverse drug reactions are over diagnosed and over reported • Nonpruritic, nonurticarial rashes occur in up to 10% of patients receiving penicillins. These rashes are usually not allergic and are not a contraindication to the use of a different beta-lactam • The frequently cited risk of 8 to 10% cross-reactivity between penicillins and cephalosporins is an overestimate based on studies from the 1970’s that are now considered flawed • Expect new intolerances (i.e. any allergy or adverse reaction reported in a drug allergy field) to be reported after 0.5 to 4% of all antimicrobial courses depending on the gender and specific antimicrobial. Expect a higher incidence of new intolerances in patients with three or more prior medication intolerances1 • For type-1 immediate hypersensitivity reactions (IgE-mediated), cross-reactivity among penicillins (table 1) is expected due to similar core structure and/or major/minor antigenic determinants, use not recommended without desensitization • For type-1 immediate hypersensitivity reactions, cross-reactivity between penicillins (table 1) and cephalosporins is due to similarities in the side chains; risk of cross-reactivity will only be significant between penicillins and cephalosporins with similar side chains • Only type-1 immediate hypersensitivity to a penicillin manifesting as anaphylaxis, bronchospasm,
    [Show full text]
  • Advances in Antibiotic Therapy in the Critically Ill Jean-Louis Vincent1*, Matteo Bassetti2, Bruno François3, George Karam4, Jean Chastre5, Antoni Torres6, Jason A
    Vincent et al. Critical Care (2016) 20:133 DOI 10.1186/s13054-016-1285-6 REVIEW Open Access Advances in antibiotic therapy in the critically ill Jean-Louis Vincent1*, Matteo Bassetti2, Bruno François3, George Karam4, Jean Chastre5, Antoni Torres6, Jason A. Roberts7, Fabio S. Taccone1, Jordi Rello8, Thierry Calandra9, Daniel De Backer10, Tobias Welte11 and Massimo Antonelli12 In this review, we briefly highlight the importance of Abstract early infection diagnosis before discussing some of the Infections occur frequently in critically ill patients and key issues related to antibiotic management, including their management can be challenging for various problems associated with timing, duration, and dosing. reasons, including delayed diagnosis, difficulties We also briefly consider ventilator-associated pneumonia identifying causative microorganisms, and the high (VAP), the use of inhaled antibiotics, and new antibiotic prevalence of antibiotic-resistant strains. In this and adjunct strategies for the future. We focus on bacter- review, we briefly discuss the importance of early ial infections and issues associated with multi-drug resist- infection diagnosis, before considering in more detail ance will not be covered. some of the key issues related to antibiotic management in these patients, including controversies surrounding use of combination or monotherapy, duration of therapy, Diagnosis and de-escalation. Antibiotic pharmacodynamics and The diagnosis of infection in critically ill patients and pharmacokinetics, notably volumes of distribution and identification of causative microorganisms and their anti- clearance, can be altered by critical illness and can biotic susceptibilities can be a challenge and yet early, influence dosing regimens. Dosing decisions in different appropriate antibiotic therapy is associated with improved subgroups of patients, e.g., the obese, are also covered.
    [Show full text]
  • The Use of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities
    University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Graduate School Professional Papers 2010 The seU of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities Joshua Bryant Phillips The University of Montana Let us know how access to this document benefits ouy . Follow this and additional works at: https://scholarworks.umt.edu/etd Recommended Citation Phillips, Joshua Bryant, "The sU e of Natural Product Substrates for the Synthesis of Libraries of Biologically Active, New Chemical Entities" (2010). Graduate Student Theses, Dissertations, & Professional Papers. 1100. https://scholarworks.umt.edu/etd/1100 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. THE USE OF NATURAL PRODUCT SUBSTRATES FOR THE SYNTHESIS OF LIBRARIES OF BIOLOGICALLY ACTIVE, NEW CHEMICAL ENTITIES by Joshua Bryant Phillips B.S. Chemistry, Northern Arizona University, 2002 B.S. Microbiology (health pre-professional), Northern Arizona University, 2002 Presented in partial fulfillment of the requirements for the degree of Doctor of Philosophy Chemistry The University of Montana June 2010 Phillips, Joshua Bryant Ph.D., June 2010 Chemistry THE USE OF NATURAL PRODUCT SUBSTRATES FOR THE SYNTHESIS OF LIBRARIES OF BIOLOGICALLY ACTIVE, NEW CHEMICAL ENTITIES Advisor: Dr. Nigel D. Priestley Chairperson: Dr. Bruce Bowler ABSTRACT Since Alexander Fleming first noted the killing of a bacterial culture by a mold, antibiotics have revolutionized medicine, being able to treat, and often cure life-threatening illnesses and making surgical procedures possible by eliminating the possibility of opportunistic infection.
    [Show full text]
  • Anew Drug Design Strategy in the Liht of Molecular Hybridization Concept
    www.ijcrt.org © 2020 IJCRT | Volume 8, Issue 12 December 2020 | ISSN: 2320-2882 “Drug Design strategy and chemical process maximization in the light of Molecular Hybridization Concept.” Subhasis Basu, Ph D Registration No: VB 1198 of 2018-2019. Department Of Chemistry, Visva-Bharati University A Draft Thesis is submitted for the partial fulfilment of PhD in Chemistry Thesis/Degree proceeding. DECLARATION I Certify that a. The Work contained in this thesis is original and has been done by me under the guidance of my supervisor. b. The work has not been submitted to any other Institute for any degree or diploma. c. I have followed the guidelines provided by the Institute in preparing the thesis. d. I have conformed to the norms and guidelines given in the Ethical Code of Conduct of the Institute. e. Whenever I have used materials (data, theoretical analysis, figures and text) from other sources, I have given due credit to them by citing them in the text of the thesis and giving their details in the references. Further, I have taken permission from the copyright owners of the sources, whenever necessary. IJCRT2012039 International Journal of Creative Research Thoughts (IJCRT) www.ijcrt.org 284 www.ijcrt.org © 2020 IJCRT | Volume 8, Issue 12 December 2020 | ISSN: 2320-2882 f. Whenever I have quoted written materials from other sources I have put them under quotation marks and given due credit to the sources by citing them and giving required details in the references. (Subhasis Basu) ACKNOWLEDGEMENT This preface is to extend an appreciation to all those individuals who with their generous co- operation guided us in every aspect to make this design and drawing successful.
    [Show full text]
  • Β-Lactam/Β-Lactamase Inhibitors for the Treatment of Infections Caused by Extended-Spectrum Β-Lactamase (ESBL)-Producing Enterobacteriaceae
    β-lactam/β-lactamase Inhibitors for the Treatment of Infections Caused by Extended-Spectrum β-Lactamase (ESBL)-producing Enterobacteriaceae Alireza FakhriRavari, Pharm.D. PGY-2 Pharmacotherapy Resident Controversies in Clinical Therapeutics University of the Incarnate Word Feik School of Pharmacy San Antonio, Texas November 13, 2015 Learning Objectives At the completion of this activity, the participant will be able to: 1. Describe different classes of β-lactamases produced by gram-negative bacteria. 2. Identify β-lactamase inhibitors and their spectrum of inhibition of β-lactamases. 3. Evaluate the evidence for use of β-lactam/β-lactamase inhibitors compared to carbapenems for treatment of ESBL infections. β-lactam/β-lactamase inhibitors for the treatment of infections caused by ESBL-producing Enterobacteriaceae 1 1. A Brief History of the Universe A. Timeline: 1940s a. β-lactams and β-lactamases i. Sir Alexander Fleming discovered penicillin from Penicillium notatum (now Penicillium chrysogenum) in 1928.1,2 ii. Chain, Florey, et al isolated penicillin in 1940, leading to its commercial production.3 iii. First β-lactamase was described as a penicillinase in Escherichia coli in 1940.4 iv. Giuseppe Brotzu discovered cephalosporin C from the mold Cephalosporin acremonium (now Acremonium chrysogenum) in 1945, but cephalosporins were not clinically used for another 2 decades.2,5 b. What are β-lactamases? i. β-lactamases are enzymes that hydrolyze the amide bond of the β-lactam ring, thereby inactivating them.6 Figure 1: Mechanism of action of β-lactamases ii. β-lactamase production is the principal mechanism by which gram-negative bacteria resist β-lactam antibiotics.6 iii.
    [Show full text]
  • Chemistry Classification Pharmacokinetics Clinical Uses And
    Available online www.jocpr.com Journal of Chemical and Pharmaceutical Research, 2014, 6(11):28-58 ISSN : 0975-7384 Review Article CODEN(USA) : JCPRC5 Chemistry, classification, pharmacokinetics, clinical uses and analysis of beta lactam antibiotics: A review Mamdouh S. Masoud a, Alaa E. Ali b* and Nessma M. Nasr c aChemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt bChemistry Department, Faculty of Science, Damanhour University, Damanhour, Egypt cStudents’ Hospital, Alexandria University, Alexandria, Egypt _____________________________________________________________________________________________ ABSTRACT This review attempts to pinpoint the importance of betalactam antibiotics, which encompass penicillins, cephalosporins, cephamycins, carbapenems and monobactams from its chemistry, classification, pharmacokinetics, clinical uses and analysis. β- lactam antibiotics have been used for treatment of bacterial infections. Most antibacterials are chemically semisynthetic modifications of various natural compounds and classified on the basis of chemical /biosynthetic origin into natural, semisynthetic, and synthetic. Also, this classification system is based on biological activity; that antibacterials are divided into two broad groups according to their biological effect on microorganisms, bactericidal agents kill bacteria, and bacteriostatic agents slow down bacterial growth. Keywords: Beta lactam Antibiotics, Classification, Pharmacokinetics, Clinical uses, Analysis. _____________________________________________________________________________________________
    [Show full text]