Antibiotics and Antibiotic Resistance

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Microbiology and Immunology
Microbiology and Immunology 2500A/B

Lecture 4: Antibiotics and Antibiotic Resistance 09/14/2012 Antimicrobial Agents  A chemical compound that kills or inhibits the growth of microorganisms  Disinfectants – antimicrobial agents that are applied to inanimate objects (e.g. floors, tables, walls, etc.)  Antiseptics – antimicrobial agents that are sufficiently nontoxic to be applied to living tissues (e.g. hand sanitizers)  Antibiotics – antimicrobial agents produced by bacteria and fungi that are exploited by humans (delivered topically and internally)  Nature is the best producer of antibacterial compounds Alexander Fleming (1881 – 1955)  Discovered penicillin in 1928  Produced from Penicillium notatum  Found colonies of staphylococci couldn't grow around a contaminating mold  Nobel Prize in Physiology and Medicine (1945) Antibiotics  Antibiotics represent one of our most effective therapeutics against bacterial infections  The availability of antibiotics enables cancer chemotherapy, organ transplantation, all invasive surgeries  Bacterial endocarditis – infection of heart valves  Two major problems: o Bacterial resistance to antibiotics always happens o Diminished interest from pharmaceutical companies to develop new antibiotics - lifetime of antibiotics is very short, especially relative to the time it takes to make them – pharmacies are rather interested in drugs that people are most likely to use on a long-term basis such as Viagra or hair-loss drugs Antibiotic Resistance is Ancient  Antibiotics (and antibiotic resistance) have been around for a very long time, far before the use of antibiotics in a clinical setting  Ancient DNA from frozen permafrost (about 30,000 years old) has found antibiotic resistance genes How do Antibiotics Work?  Antibiotics either kill bacteria, or stop them from growing  For bacteriostatic antibiotics, the immune system must take over to kill the bacteria  Bacteriostatic – stops growth of infection  Bacteriocidal – infection dies Measuring Antibiotic Activity  Minimum inhibitory concentration (MIC) o Series of culture tubes with varying concentration of agent o Check for visible growth o MIC = lowest concentration of agent that inhibits growth  Modern minimum inhibitory concentration (MIC) o Antibiotic strips o Faster, multiple antibiotics How do Antibiotics Work?  Antibiotics target essential bacterial components: o Cell wall synthesis o Protein synthesis o DNA/RNA synthesis o Folate synthesis o Cell membrane alteration  Targets are not present (or different) in eukaryotic cells -Lactam Antibiotics Example – Penicillin  Contain a "-lactam ring"  Functions to inhibit cell wall synthesis in bacteria  -lactams bind the bacterial "penicillin- binding proteins (PBPs)" o PBPs are transpeptidases o No peptide cross-links = weak cell wall = cell death  But some bacteria can produce a -lactamase o An enzyme that destroys the ring and thus the antibiotic Example – Methicillin  Contain a "-lactam ring"  Chemically modified penicillin  Can’t be cleaved by -lactamases  But some bacteria can produce a different “penicillin-binding protein” (e.g. PBP2a) – encoded by ‘mec’  PBP2a doesn’t bind methicillin (or other - lactams)  Becomes pan-resistant – resistant to anything that contains -lactam Vancomycin  Inhibits cell wall synthesis in gram positives  Glycopeptide antibiotic  targets gram positive bacteria (can't get through the outer membrane in gram negatives)  Often a drug of "last resort" (e.g. HA-MRSA) – HA = hospital acquired  Resistance is encoded by the van genes  Vancomycin binds the peptide linkage at terminal D-Ala-D-Ala residues and inhibits transpeptidation  Resistance genes change these to D-Ala-D-Lac and vancomycin can no longer bind Protein Synthesis Inhibitors  Bacteria contain 70S (30S + 50S) ribosomes  Eukaryotes contain 80S (40S + 60S) ribosomes  Many antibiotics target bacterial ribosomes and block translation o 50S inhibitors (e.g. Erythromycin, Chloramphenicol) o 30S inhibitors (e.g. Tetracycline, Kanamycin) Folic Acid Synthesis Inhibitors  Examples - Trimethoprim and Sulfonamides  Folic acid is a vitamin (B9) for humans  Bacteria need folic acid for thymidine synthesis  Bacteria cannot absorb folic acid so they must synthesize their own  Inhibition of folic acid synthesis blocks DNA replication DNA/RNA Synthesis Inhibitors 
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