20181_MCB2010_Microbiology ch10-lecture.pdf

PowerPoint® Lecture Presentations prepared by Mindy Miller-Kittrell, North Carolina State University...

PowerPoint® Lecture Presentations prepared by Mindy Miller-Kittrell, North Carolina State University CHAPTER 10 Controlling Microbial Growth in the Body: Antimicrobial Drugs © 2018 Pearson Education, Inc.  The History of Antimicrobial Agents Drugs Chemicals that affect physiology in any manner Chemotherapeutic agents Drugs that act against diseases Antimicrobial agents (antimicrobials) Drugs that treat infections © 2018 Pearson Education, Inc.  The History of Antimicrobial Agents Paul Ehrlich “Magic bullets” Arsenic compounds that killed microbes Alexander Fleming Penicillin released from Penicillium Gerhard Domagk Discovered sulfanilamide Selman Waksman Antibiotics Antimicrobial agents produced naturally by organisms © 2018 Pearson Education, Inc.  Figure 10.1 Antibiotic effect of the mold Penicillium chrysogenum. © 2018 Pearson Education, Inc.  The History of Antimicrobial Agents Semisynthetics Chemically altered antibiotics that are more effective, longer lasting, or easier to administer than naturally occurring ones Synthetics Antimicrobials that are completely synthesized in a lab © 2018 Pearson Education, Inc.  Table 10.1 Sources of Some Common Antibiotics and Semisynthetics © 2018 Pearson Education, Inc.  The History of Antimicrobial Agents Tell Me Why Why aren’t antibiotics effective against the common cold? © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Successful chemotherapy requires selective toxicity Antibacterial drugs constitute largest number and diversity of antimicrobial agents Fewer drugs to treat eukaryotic infections Antiviral drugs limited © 2018 Pearson Education, Inc.  Figure 10.2 Mechanisms of action of microbial drugs. © 2018 Pearson Education, Inc.  Chemotherapeutic Agents: Modes of Action © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Cell Wall Synthesis Inhibition of synthesis of bacterial walls Most common agents prevent cross-linkage of NAM subunits Beta-lactams are most prominent in this group Functional groups are beta-lactam rings Beta-lactams bind to enzymes that cross-link NAM subunits Bacteria have weakened cell walls and eventually lyse © 2018 Pearson Education, Inc.  Figure 10.3a-b Bacterial cell wall synthesis and the inhibitory effects of beta- lactams on it. © 2018 Pearson Education, Inc.  Figure 10.3c-e Bacterial cell wall synthesis and the inhibitory effects of beta- lactams on it. © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Cell Wall Synthesis Inhibition of synthesis of bacterial walls Semisynthetic derivatives of beta-lactams More stable in acidic environments More readily absorbed Less susceptible to deactivation More active against more types of bacteria © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Cell Wall Synthesis Inhibition of synthesis of bacterial walls Vancomycin and cycloserine Interfere with particular bridges that link NAM subunits in many Gram-positive bacteria Bacitracin Blocks transport of NAG and NAM from cytoplasm Isoniazid and ethambutol Disrupt mycolic acid formation in mycobacterial species © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Cell Wall Synthesis Inhibition of synthesis of bacterial walls Prevent bacteria from increasing amount of peptidoglycan Have no effect on existing peptidoglycan layer Effective only for growing cells © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Cell Wall Synthesis Inhibition of synthesis of fungal walls Fungal cells composed of various polysaccharides not found in mammalian cells Echinocandins inhibit the enzyme that synthesizes glucan © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Protein Synthesis Interference with prokaryotic ribosomes Prokaryotic ribosomes are 70S (30S and 50S) Eukaryotic ribosomes are 80S (40S and 60S) Drugs can selectively target translation Mitochondria of animals and humans contain 70S ribosomes Can be harmful © 2018 Pearson Education, Inc.  Figure 10.4 Some mechanisms by which antimicrobials target prokaryotic ribosomes to inhibit protein synthesis. © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Protein Synthesis Interference with charging of transfer RNA molecules Aminoacyl-tRNA synthetases load amino acids onto tRNA molecules Mupirocin selectively binds to isoleucyl-tRNA synthetase Prevents loading of isoleucine only in Gram-positive bacteria © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Disruption of Cytoplasmic Membranes Some drugs form channel through cytoplasmic membrane and damage its integrity Nystatin and amphotericin B attach to ergosterol in fungal membranes Humans somewhat susceptible because cholesterol similar to ergosterol Bacteria lack sterols; not susceptible © 2018 Pearson Education, Inc.  Figure 10.5 Disruption of the cytoplasmic membrane by the antifungal amphotericin B. © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Disruption of Cytoplasmic Membranes Azoles and allylamines inhibit ergosterol synthesis Polymyxin disrupts cytoplasmic membranes of Gram-negative bacteria Toxic to human kidneys Some parasitic drugs act against cytoplasmic membranes © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Metabolic Pathways Antimetabolic agents can be effective when pathogen and host metabolic processes differ Atovaquone interferes with electron transport in protozoa and fungi Heavy metals inactivate enzymes Agents that disrupt tubulin polymerization and glucose uptake by many protozoa and parasitic worms Drugs that block activation of viruses Metabolic antagonists © 2018 Pearson Education, Inc.  Figure 10.6 The antimetabolic action of sulfonamides in inhibiting nucleic acid synthesis. © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Metabolic Pathways Trimethoprim also interferes with nucleotide synthesis. Antiviral agents can target unique aspects of viral metabolism. Amantadine, rimantadine, and weak organic bases prevent viral uncoating. Protease inhibitors interfere with an enzyme that HIV needs in its replication cycle. © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Nucleic Acid Synthesis Several drugs block DNA replication or RNA transcription Drugs often affect both eukaryotic and prokaryotic cells Not normally used to treat infections Used in research and perhaps to slow cancer cell replication © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Nucleic Acid Synthesis Quinolones and fluoroquinolones Act against prokaryotic DNA gyrase Nucleotide or nucleoside analogs Interfere with function of nucleic acids Distort shapes of nucleic acid molecules and prevent further replication, transcription, or translation Most often used against viruses Effective against rapidly dividing cancer cells © 2018 Pearson Education, Inc.  Figure 10.7 Nucleosides and some of their antimicrobial analogs. © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Inhibition of Nucleic Acid Synthesis Inhibitors of RNA polymerase Reverse transcriptase inhibitors Act against an enzyme HIV uses in its replication cycle Do not harm people because humans lack reverse transcriptase © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Prevention of Virus Attachment, Entry, or Uncoating Attachment antagonists block viral attachment or receptor proteins New area of antimicrobial drug development Pleconaril blocks viral attachment Arildone prevents viral uncoating © 2018 Pearson Education, Inc.  Mechanisms of Antimicrobial Action Tell Me Why Some antimicrobial drugs are harmful to humans. Why can physicians safely prescribe such drugs despite the potential danger? © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Ideal Antimicrobial Agent Readily available Inexpensive Chemically stable Easily administered Nontoxic and nonallergenic Selectively toxic against wide range of pathogens © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Spectrum of Action Number of different pathogens a drug acts against Narrow-spectrum effective against few organisms Broad-spectrum effective against many organisms May allow for secondary or superinfections to develop Killing of normal flora reduces microbial antagonism © 2018 Pearson Education, Inc.  Figure 10.8 Spectrum of action for selected antimicrobial agents. © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Effectiveness Ascertained by Diffusion susceptibility test Minimum inhibitory concentration test Minimum bactericidal concentration test © 2018 Pearson Education, Inc.  Figure 10.9 Zones of inhibition in a diffusion susceptibility (Kirby-Bauer) test. © 2018 Pearson Education, Inc.  Figure 10.10 Minimum inhibitory concentration (MIC) test in wells. © 2018 Pearson Education, Inc.  Figure 10.11 An Etest, which combines aspects of Kirby-Bauer and MIC tests. © 2018 Pearson Education, Inc.  Figure 10.12 A minimum bactericidal concentration (MBC) test. © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Routes of Administration Topical application of drug for external infections Oral route requires no needles and is self-administered Intramuscular administration delivers drug via needle into muscle Intravenous administration delivers drug directly to bloodstream Must know how antimicrobial agent will be distributed to infected tissues © 2018 Pearson Education, Inc.  Figure 10.13 The effect of route of administration on blood levels of a chemotherapeutic agent. © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Safety and Side Effects Toxicity Cause of many adverse reactions poorly understood Drugs may be toxic to kidneys, liver, or nerves Consideration needed when prescribing drugs to pregnant women Therapeutic index is the ratio of the dose of a drug that can be tolerated to the drug's effective dose © 2018 Pearson Education, Inc.  Figure 10.14 Some side effects resulting from toxicity of antimicrobial agents. © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Safety and Side Effects Allergies Allergic reactions are rare but may be life threatening Anaphylactic shock Disruption of normal microbiota May result in secondary infections Overgrowth of normal flora causing superinfections Of greatest concern for hospitalized patients © 2018 Pearson Education, Inc.  Clinical Considerations in Prescribing Antimicrobial Drugs Tell Me Why Why don’t physicians invariably prescribe the antimicrobial with the largest zone of inhibition? © 2018 Pearson Education, Inc.  Resistance to Antimicrobial Drugs The Development of Resistance in Populations Some pathogens are naturally resistant Resistance by bacteria acquired in two ways: New mutations of chromosomal genes Acquisition of R plasmids via transformation, transduction, and conjugation © 2018 Pearson Education, Inc.  Figure 10.15 The development of a resistant strain of bacteria. © 2018 Pearson Education, Inc.  Antibiotic Resistance: Origins of Resistance © 2018 Pearson Education, Inc.  Resistance to Antimicrobial Drugs Mechanisms of Resistance At least seven mechanisms of microbial resistance Produce enzyme that destroys or deactivates drug Slow or prevent entry of drug into the cell Alter target of drug so it binds less effectively Alter their own metabolic chemistry Pump antimicrobial drug out of the cell before it can act Bacteria in biofilms can resist antimicrobials Mycobacterium tuberculosis produces MfpA protein Binds DNA gyrase, preventing the binding of fluoroquinolone drugs © 2018 Pearson Education, Inc.  Figure 10.16 How beta-lactamase (penicillinase) renders penicillin inactive. © 2018 Pearson Education, Inc.  Antibiotic Resistance: Forms of Resistance © 2018 Pearson Education, Inc.  Interactive Microbiology In the Interactive Microbiology tutorial in Chapter 10, we learn about antibiotic resistance. Rebecca enters the hospital to have an appendectomy but becomes sick with pneumonia. Her pneumonia is caused by Klebsiella pneumoniae. Antimicrobial drugs bind to and disrupt specific bacterial components. Bacteria such as K. pneumoniae can resist antimicrobials through several mechanisms. © 2018 Pearson Education, Inc.  Resistance to Antimicrobial Drugs Multiple Resistance and Cross Resistance Pathogen can acquire resistance to more than one drug Common when R plasmids exchanged Develop in hospitals and nursing homes Constant use of drugs eliminates sensitive cells Multiple-drug-resistant pathogens are resistant to at least three antimicrobial agents Cross resistance can occur when drugs are similar in structure © 2018 Pearson Education, Inc.  Resistance to Antimicrobial Drugs Retarding Resistance Maintain high concentration of drug in patient for sufficient time Inhibit the pathogen so immune system can eliminate Use antimicrobial agents in combination Synergism occurs when one drug enhances the effect of a second drug Antagonism occurs when drugs interfere with each other © 2018 Pearson Education, Inc.  Figure 10.17 An example of synergism between two antimicrobial agents. © 2018 Pearson Education, Inc.  Resistance to Antimicrobial Drugs Retarding Resistance Use antimicrobials only when necessary Develop new variations of existing drugs Second-generation drugs Third-generation drugs Search for new antibiotics, semisynthetics, and synthetics Bacteriocins Design drugs complementary to the shape of microbial proteins to inhibit them © 2018 Pearson Education, Inc.  Resistance to Antimicrobial Drugs Tell Me Why Why is it incorrect to say that an individual bacterium develops resistance in response to an antibiotic? © 2018 Pearson Education, Inc.