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9: Antimicrobial Drugs - Biology

9: Antimicrobial Drugs - Biology


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Chapter 9 BSC 3271 Learning Outcomes

  • Tell the story of the discovery of antibiotics, including who discovered antibiotics, when, how, and the name of the first antibiotic discovered.
  • Define antibiotic and identify the specific group of microbes targeted by antibiotics.
  • Identify major targets of antibiotics and explain why disruption of each will cause microbial death or inactivation.
  • Describe desirable features of an antibiotic that would be used to treat infection.
  • Analyze a situation to identify the most suitable antibiotic/chemotherapy choice.
  • Explain the possible natural role of antibiotics in the environment and give an example of one bacterial genus that produces many clinically relevant antibiotics.
  • Describe the mode of action of beta-lactam antibiotics, including cellular structure impaired, what enzyme is inhibited and how that leads to impairment of cellular structure, consequences of impaired cellular structure, and whether growing cells are more easily killed or not and why.
  • Identify the cellular targets of the following antimicrobial drugs: beta-lactams, aminoglycosides, polymyxins, azoles, nucleotide analogs, and quinolones and which microbial groups they target (broad range, narrow range, which group(s) if narrow range) (which ones?).
  • Know to which class of antimicrobial drugs penicillins, cephalosporins, carbapenems, streptomycin, colistin, fluconazole, acyclovir, and ciprofloxacin belong (beta-lactam, aminoglycoside, azole, polymyxin, or quinolone).
  • By its name, determine if an antibiotic is a penicillin, cephalosporin, or carbapenem.
  • By its name, determine whether an antibiotic is produced by Streptomyces
  • Explain the five common mechanisms of antibiotic resistance.
  • Describe the mechanism of beta-lactamase, including what kind of antibiotics this enzyme provides resistance to, how it provides resistance, and how the compound clavulanic acid counteracts beta-lactamase.
  • Explain why Pseudomonas species are naturally resistant to many different antibiotics.
  • Explain how natural selection leads to the emergence of antibiotic resistant strains of microbes.
  • List several human-controlled factors that contribute to the emergence of antibiotic resistance, including how antibiotics are used in health care and in agriculture.
  • Recognize the following abbreviations of antibiotic resistant pathogens and what the abbreviations stand for: MRSA, VRSA, VRE, CRE, MDR-TB, XDR-TB.
  • Describe strategies to reduce the spread of antibiotic resistance that can be used by 1. health care workers and 2. individuals.
  • Describe viral replication of HIV and how the replication mechanism can result in the development of drug resistance, particularly in the case of the nucleotide analog AZT.
  • Explain how the major anti-HIV drugs work and the advantages to using combination drug therapy.
  • 9.1: Discovering Antimicrobial Drugs
    Antimicrobial drugs produced by purposeful fermentation and/or contained in plants have been used as traditional medicines in many cultures for millennia. The purposeful and systematic search for a chemical “magic bullet” that specifically target infectious microbes was initiated by Paul Ehrlich in the early 20th century. The discovery of the natural antibiotic, penicillin, by Alexander Fleming in 1928 started the modern age of antimicrobial discovery and research.
  • 9.2: Clinical Considerations
    Antimicrobial drugs can be bacteriostatic or bactericidal, and these characteristics are important considerations when selecting the most appropriate drug. The use of narrow-spectrum antimicrobial drugs is preferred in many cases to avoid superinfection and the development of antimicrobial resistance. Broad-spectrum antimicrobial use is warranted for serious systemic infections when there is no time to determine the causative agent or when narrow-spectrum antimicrobials fail.
  • 9.3: Antibiotics
    Antibacterial compounds exhibit selective toxicity, largely due to differences between prokaryotic and eukaryotic cell structure. Cell wall synthesis inhibitors, including the β-lactams, the glycopeptides, and bacitracin, interfere with peptidoglycan synthesis, making bacterial cells more prone to osmotic lysis. There are a variety of broad-spectrum, bacterial protein synthesis inhibitors that selectively target the prokaryotic 70S ribosome, including those that bind to the 30S and 50S subunits.
  • 9.4: Drugs Targeting Other Pathogens
    Because fungi, protozoans, and helminths are eukaryotic organisms like human cells, it is more challenging to develop antimicrobial drugs that specifically target them. Similarly, it is hard to target viruses because human viruses replicate inside of human cells.
  • 9.5: Antibiotic Resistance
    Antimicrobial resistance is on the rise and is the result of selection of drug-resistant strains in clinical environments, the overuse and misuse of antibacterials, the use of subtherapeutic doses of antibacterial drugs, and poor patient compliance with antibacterial drug therapies. Drug resistance genes are often carried on plasmids or in transposons that can undergo vertical transfer easily and between microbes through horizontal gene transfer.
    • 9.5.1: Cost and Prevention of Resistance
    • 9.5B: Antibiotic Misuse
    • 9.5D: Biofilms, Persisters, and Antibiotic Tolerance
    • 9.5E: Finding New Antimicrobial Drugs
  • 9.6: Testing Drug Effectivenes
    The Kirby-Bauer disk diffusion test helps determine the susceptibility of a microorganism to various antimicrobial drugs. However, the zones of inhibition measured must be correlated to known standards to determine susceptibility and resistance, and do not provide information on bactericidal versus bacteriostatic activity, or allow for direct comparison of drug potencies. Antibiograms are useful for monitoring local trends in antimicrobial resistance/susceptibility.

Thumbnail: Staphylococcus aureus - Antibiotics Test plate. (Public Domain; CDC / Provider: Don Stalons).


Targeting virulence: a new paradigm for antimicrobial therapy

Clinically significant antibiotic resistance has evolved against virtually every antibiotic deployed. Yet the development of new classes of antibiotics has lagged far behind our growing need for such drugs. Rather than focusing on therapeutics that target in vitro viability, much like conventional antibiotics, an alternative approach is to target functions essential for infection, such as virulence factors required to cause host damage and disease. This approach has several potential advantages including expanding the repertoire of bacterial targets, preserving the host endogenous microbiome, and exerting less selective pressure, which may result in decreased resistance. We review new approaches to targeting virulence, discuss their advantages and disadvantages, and propose that in addition to targeting virulence, new antimicrobial development strategies should be expanded to include targeting bacterial gene functions that are essential for in vivo viability. We highlight both new advances in identifying these functions and prospects for antimicrobial discovery targeting this unexploited area.


Cell biology of microbes and pharmacology of antimicrobial drugs explored by Atomic Force Microscopy

Antimicrobial molecules have been used for more than 50 years now and are the basis of modern medicine. No surgery can nowdays be imagined to be performed without antibiotics dreadful diseases like tuberculosis, leprosis, siphilys, and more broadly all microbial induced diseases, can be cured only through the use of antimicrobial treatments. However, the situation is becoming more and more complex because of the ability of microbes to adapt, develop, acquire, and share mechanisms of resistance to antimicrobial agents. We choose to introduce this review by briefly drawing the panorama of antimicrobial discovery and development, but also of the emergence of microbial resistance. Then we describe how Atomic Force Microscopy (AFM) can be used to provide a better understanding of the mechanisms of action of these drugs at the nanoscale level on microbial interfaces. In this section, we will address these questions: (1) how does drug treatment affect the morphology of single microbes? (2) do antimicrobial molecules modify the nanomechanical properties of microbes, or do the nanomechanical properties of microbes play a role in antimicrobial activity and efficiency? and (3) how are the adhesive abilitites of microbes affected by antimicrobial drugs treatment? Finally, in a second part of this review we focus on recent studies aimed at changing the paradigm of the single molecule/cell technology that AFM typically represents. Recent work dealing with the creation of a microbe array which can be explored by AFM will be presented, as these developments constitute the first steps toward transforming AFM into a higher throughput technology. We also discuss papers using AFM as NanoMechnanicalSensors (NEMS), and demonstrate the interest of such approaches in clinical microbiology to detect quickly and with high accuracy microbial resistance.

Keywords: AFM Bacteria assembly Bacterial adhesion MEMS Microbial cell wall Nanoechanic Single cell Single molecule.


9: Antimicrobial Drugs - Biology

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Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

More than 3000 antimicrobial peptides (AMPs) have been discovered, seven of which have been approved by the U.S. Food and Drug Administration (FDA). Now commercialized, these seven peptides have mostly been utilized for topical medications, though some have been injected into the body to treat severe bacterial infections. To understand the translational potential for AMPs, we analyzed FDA-approved drugs in the FDA drug database. We examined their physicochemical properties, secondary structures, and mechanisms of action, and compared them with the peptides in the AMP database. All FDA-approved AMPs were discovered in Gram-positive soil bacteria, and 98% of known AMPs also come from natural sources (skin secretions of frogs and toxins from different species). However, AMPs can have undesirable properties as drugs, including instability and toxicity. Thus, the design and construction of effective AMPs require an understanding of the mechanisms of known peptides and their effects on the human body. This review provides an overview to guide the development of AMPs that can potentially be used as antimicrobial drugs.

Keywords: FDA-approved peptides antibiotic resistance antibiotics antimicrobial peptides peptide therapeutics rational protein design.


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Keywords: antimicrobial drugs, biological engineering, synthetic biology, chemical synthesis methods, metabolic engineering

Citation: Dhakal D and Sohng JK (2017) Coalition of Biology and Chemistry for Ameliorating Antimicrobial Drug Discovery. Front. Microbiol. 8:734. doi: 10.3389/fmicb.2017.00734

Received: 03 January 2017 Accepted: 10 April 2017
Published: 04 May 2017.

Tzi Bun Ng, The Chinese University of Hong Kong, Hong Kong

Anjan Debnath, University of California, San Diego, USA
Ayush Kumar, University of Manitoba, Canada
Ahmed A. Al-Amiery, National University of Malaysia, Malaysia

Copyright © 2017 Dhakal and Sohng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


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