Antimicrobial Drugs Lecture PDF

Antimicrobial Drugs  Learning outcomes Understand name and compare are the mechanisms of antimicrobial action Define the characteristics of antimicrobial drugs Explain how some microbes resistant to antimicrobial drugs Name some examples of specific antimicrobial drugs and how...

Antimicrobial Drugs  Learning outcomes Understand name and compare are the mechanisms of antimicrobial action Define the characteristics of antimicrobial drugs Explain how some microbes resistant to antimicrobial drugs Name some examples of specific antimicrobial drugs and how do they work What is an antimicrobial? An antimicrobial is an agent that kills microorganisms Kills = microbiocidal or stops their growth Prevents growth = microbiostatic Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. An antimicrobial drug will work against one type of organism  Principles of Drug Action Drugs alter physiological activity Must reach their intended target site in appropriate concentration Involves processes - pharmacokinetics Drug administration Absorption Distribution Biotransformation Clearance Mosby items and derived items © 2010 by Mosby, Inc., an affiliate of Elsevier Inc. Drug administration Drugs are administered enterally – via the digestive route or parenterally via any other system Absorption Absorption = rate at which the drug leaves its site of administration and extent of which it Appears at the site of action Drug has to be dissolved in body fluids Pass through biological barriers Drug Distribution Transfer of drugs across biological membranes into body compartments Depending on drug’s chemical properties, solubility, blood flow, molecular size, and excretion Water soluble drugs are readily excreted Blood-brain barrier is an obstacle Placenta is a pathway for transfer Mosby items and derived items © 2010 by Mosby, Inc., an affiliate of Elsevier Inc. Bio transformation Involves the metabolism of a drug Liver plays major role in drug metabolism Other organs involved are: lungs, kidney, and adrenal glands Lipid soluble drugs Drug metabolites need to be water soluble for elimination by the kidneys Clearance Primarily via kidneys Glomerular filtration Tubular reabsorption Tubular secretion Some drugs are metabolized in the liver and excreted via bile Mosby items and derived items © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.  Mechanisms of Antimicrobial Action Goal: Disruption of metabolism or structure of organism so it cannot survive or reproduce Microbicidal Kills microbes Can kill normal flora— potential for superinfection Bacteriolytic: lyses the cells Microbiostatic Reversibly inhibits growth Brock Biology of Microorganisms, Global Editiony Michael T. Madigan; Kelly S. Bender; Daniel H. Buckley; W. Matthew Sattley; David A. Stahl 2018  Spectrum of Action Broad spectrum Effective against a large variety of microorganisms Narrow spectrum Effective against relatively small variety of organisms Avoids damage to normal flora Medium spectrum Effective against some gram-positive and gram-negative bacteria; not all Mosby items and derived items © 2010 by Mosby, Inc., an affiliate of Elsevier Inc. Antimicrobial Agents Why does one drug not do all ?  Selective toxicity An important quality for an antimicrobial drug is selective toxicity, meaning that it selectively kills or inhibits the growth of microbial targets while causing minimal or no harm to the host. Prokaryotic targets vs Eukaryotic Most antimicrobial drugs currently in clinical use are antibacterial because the prokaryotic cell provides a greater variety of unique targets for selective toxicity, in comparison to fungi, parasites, and viruses. Selective toxicity is achievable as the drug accumulates in the microbe to a higher level or it is specific to a structure/function of the target microorganism. Each class of antibacterial drugs has a unique mode of action (the way in  Inhibition of Cell Wall biosynthesis β-Lactam antibiotics are bactericidal agents that interrupt and block bacterial cell-wall formation They form covalent bonds with essential penicillin-binding proteins (PBPs), enzymes that are involved in the terminal steps of peptidoglycan cross-linking in both Gram-negative and Gram- positive bacteria. = vulnerable to lysis Penicillin is the classic example Excellent example of selective toxicity as only bacterial cells contain peptidoglycan Brock Biology of Microorganisms, Global Editiony Michael T. Madigan; Kelly S. Bender; Daniel H. Buckley; W. Matthew Sattley; David A. Stahl 2018  Inhibition of Protein Synthesis Disruption of translation at ribosome Eukaryotic ribosomes/cells not affected the cytoplasmic ribosomes found in animal cells are structurally distinct from those found in bacterial cells, making protein biosynthesis a good selective target for antibacterial drugs Brock Biology of Microorganisms, Global Editiony Michael T. Madigan; Kelly S. Bender; Daniel H. Buckley; W. Matthew Sattley; David A. Stahl 2022  Disruption of Plasma Membrane A small group of antibacterials target the bacterial membrane as their mode of action - the polymyxins only polymyxin B and polymyxin E (colistin) have been used clinically. They are lipophilic with detergent-like properties and interact with the lipopolysaccharide component of the outer membrane of gram- negative bacteria, ultimately disrupting both their outer and inner membranes and killing the bacterial cells. membrane-targeting mechanism is not a selective toxicity, and these drugs also target and damage the membrane of cells in the kidney and nervous system when administered systemically..  Inhibition of Nucleic Acid Synthesis Disruption of the synthesis of nucleotide components Inhibition of DNA replication Interference with RNA transcription End result is the same Competitive inhibition Quinolone antibiotics interfere with changes in DNA supercoiling by binding to topoisomerase II or topoisomerase IV. This leads to the formation of double-stranded DNA breaks and cell death in either a protein synthesis-dependent or protein synthesis-independent manner.  Inhibition of Metabolic Pathways Some drugs function as antimetabolites, competitive inhibitors for bacterial metabolic enzymes. Disruption of numerous cellular metabolic processes Including folic acid synthesis Disruption of enzyme activity/production Disruption of essential metabolic compounds Sulfonamides/ Trimethoprim block bacterial biosynthesis of folic acid and, subsequently, pyrimidines and purines (nucleotides) required for nucleic acid synthesis. Resistance to Antimicrobial Drugs Key Causes of AMR: Over-prescription of antimicrobials. Shortened courses or incomplete compliance with antimicrobial treatment. Antimicrobial overuse in livestock and fish farming. Poor infection control in health care settings. Poor hygiene and sanitation. Limited discovery of new antimicrobials. Resistance to Antimicrobial Drugs Changes in membrane permability Increased drug elimination Changes in the target or receptor Change in metabolic pathway Change in previously inhibited enzyme Development of defensive enzymes Resistance to Antimicrobial Drugs Zone of inhibition based on diffusion of molecules Diameters are measured to determine effectiveness Acquisition of Drug Resistance  Multiple Resistances Global problem Due to improper use of prescribed antibiotics Primarily develop in healthcare facilities “Superbugs” Cross-resistance Brock Biology of Microorganisms, Global Editiony Michael T. Madigan; Kelly S. Bender; Daniel H. Buckley; W. Matthew Sattley; David A. Stahl 2022 Preventing Drug Resistance  Antiviral Agents Most viruses have no cure Limited in effectiveness Resistance a problem, due to RNA genomes and fast replication rates Often damages host cells Target points in viral life cycle Prevent penetration Block transcription/translation Prevent maturation of virus http://cenm.ag/antiviralhistory.  Antifungal Agents Fungi Eukaryotic cells—many side effects possible Synthetic Synthetic azoles—superficial infections Flucytosine—systemic infections and cutaneous mycoses Natural Macrolide polyene antibiotics— systemic mycoses Griseofulvin—localized dermatophyte infections Echinocandins—systemic fungal infections Brock Biology of Microorganisms, Global Editiony Michael T. Madigan; Kelly S. Bender; Daniel H. Buckley; W. Matthew Sattley; David A. Stahl 2022  Antifungal Agents Mechanism of action of antifungal drugs https://www.youtube.com/watch?  Antiprotozoal Agents Chloroquine and primaquine Synthetic—derived from quinine Used in Plasmodium infections Plasmodium causes malaria Metronidazole Used in the treatment of Trichomonas vaginal infections and gastrointestinal infection caused Giardia Pyrimethamine Used to prevent and treat malaria when used with sulfanilamide Can also treat toxoplasmosis Quinine Nonsynthetic Extracted from the bark of cinchona trees Used in the treatment of malaria Mosby items and derived items © 2010 by Mosby, Inc., an affiliate of Elsevier Inc.  Antihelminthic Agents Helminths are eukaryotic and treatment is difficult—most agents are designed to suppress helminths’ metabolism or movement Niclosamide Mebendazole Piperazine Ivermectin How can we solve the antibiotic resistance crisis? - Gerry Wright - YouTube