Microbio 310 1st Edition Lecture 22Outline of Last Lecture I. Facts about Antibiotics/ResistanceII. 26.1 Heat SterilizationIII. 26.2 Radiation SterilizationIV. 26.3 Filter SterilizationV. 26.4 Chemical Growth ControlOutline of Current Lecture I. Antimicrobial Agents Used In VivoII. 26.6 Synthetic Antimicrobial DrugsIII. 26.7 Naturally Occurring Antimicrobial Drugs: AntibioticsIV. 26.8 beta-Lactam Antibiotics: Penicillins and CephalosporinsV. 26.10 Antiviral DrugsVI. 26.12 Antimicrobial Drug ResistanceVII. 26.13 The Search for New Antimicrobial DrugsCurrent LectureAntimicrobial Agents Used In Vivo• Classified on the basis of:– Molecular structure– Mechanism of action(ex: affect cell wall synthesis, protein synthesis)– Spectrum of antimicrobial activity These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.26.6 Synthetic Antimicrobial Drugs• Product of organic synthesis • Sulfa drugs: discovered by Gerhard Domagk in the 1930s – Inhibit growth of bacteria (inhibit nucleotide synthesis) – High Therapeutic Index* = low host toxicity – We don’t make folate so we take vitamins – Resistance bacteria learn to absorb folate from environment * Also HTI Isoniazid is a growth analog effective only against Mycobacterium – – prodrug Interferes with synthesis of mycolic acid • Nucleic acid base analogs have been formed by the addition of bromine or fluorine • Quinolones are antibacterial compounds that interfere with DNA gyrase, which unwinds DNA (ciprofloxacin CIPRO) 26.7 Naturally Occurring Antimicrobial Drugs: Antibiotics • Antibiotics are naturally produced antimicrobial agents – Less than 1% of known antibiotics are clinically useful • Can be modified to enhance efficacy (semisynthetic) • The susceptibility of microbes to different antibiotics varies greatly – Gram-positive and gram-negative bacteria vary in their sensitivity to antibiotics – Broad-spectrum antibiotics are effective against both groups of bacteria 26.8 eta-Lactam Antibiotics: Penicillins and Cephalosporins• eta -Lactam antibiotics are one of the most important groups of antibiotics of all time – Include penicillins, cephalosporins, and cephamycins– Over half of all antibiotics used worldwide • Penicillins I – Discovered by Alexander Fleming; in his experiment he saw a zone of exclusion(circle of mold) where no bacteria were growing, therefore he concluded the mold is producing antibacterialI – Primarily effective against gram-positive bacteria I – Some synthetic forms are effective against some gram-negative bacteria (Ex: Ampicillin)I – Target cell wall synthesis 26.10 Antiviral Drugs • Most antiviral drugs also target host structures, resulting in toxicity • Most successful and commonly used antivirals are the nucleoside analogs (e.g., azidothymidine aka AZT) –Block reverse transcriptase and production of viral DNA (inhibits HIV)– Also called nucleoside reverse transcriptase inhibitors (fake A’s and T’s)• Nonnucleoside reverse transcriptase inhibitors (NNRTI) bind directly to RT and inhibit reverse transcription • Protease inhibitors inhibit the processing of large viral proteins into individual components • Fusion inhibitors prevent viruses from successfully fusing with the host cell • Two categories of drugs successfully limit influenza infection: – Adamantanes– Neuraminidase inhibitors •Interferons are small proteins that prevent viral multiplication by stimulating antiviral proteins in uninfected cells26.12 Antimicrobial Drug Resistance • Antimicrobial drug resistance– The acquired ability of a microorganism to resist the effects of a chemotherapeutic agent to which it is normally sensitive • At least six reasons that microorganisms are naturally resistant to certain antibiotics:– Organism lacks structure the antibiotic inhibits – Organism is impermeable to antibiotic (waxy membrane organism-need to acid treat them to get through)– Organism can inactivate the antibiotic – Organism may modify the target of the antibiotic (mutations)– Organism may develop a resistant biochemical pathway – Organism may be able to pump out the antibiotic (efflux) • Most drug-resistant bacteria isolated from patients contain drug-resistance genes located onR plasmids • Evidence indicates that R plasmids predate the antibiotic era • The use of antibiotics in medicine, veterinary medicine, and agriculture selects for the spread of R plasmids – Many examples of overuse of antibiotics – Used far more often than necessary (e.g., antibiotics used in agriculture as supplements to animal feed) • Almost all pathogenic microbes have acquired resistance to some chemotherapeutic agents • A few pathogens have developed resistance to all known antimicrobial agents – Methicillin-resistant S. aureus (MRSA) • Resistance can be minimized by using antibiotics correctly and only when needed • Resistance to a certain antibiotic can be lost if antibiotic is not used for several years26.13 The Search for New Antimicrobial Drugs • Long-term solution to antimicrobial resistance relies on the development of new antimicrobial compounds (ex: changed CH2 to Oxygen in Vancomycin)– Modification of current antimicrobial compounds is often productive• Automated chemistry methods (combinatorial chemistry) has sped up drug discovery – 7,000,000 compounds must be screened to find a single useful clinical drug • Computers can now be used to design molecules to interact with specific microbial structures – Most successful example is saquinavir• Binds to active site of HIV protease • New methods of screening natural products are being used – Led to the discovery of platensimycin • Combinations of drugs can be used (e.g., ampicillin and sulbactambetalactamase inhibitor) – Person with AIDS can get 80% of their lifespan back by using a combination of drugs• Bacteriophage therapy- C diff – Can’t treat with antibiotics so treat with phage– Phages interact with individual bacterial cell surface components and show specificity for particular bacterial species (ex: prevents killing of good bacteria in the gut and only kills the bad bacteria, such as C