Antibiotics and Antibiotics Resistance Notes .docx

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Department
Microbiology and Immunology
Course
Microbiology and Immunology 2500A/B
Professor
John Mc Cormick
Semester
Winter

Description
Antibiotics and Antibiotics Resistance Antimicrobial Agents Disinfectants: antimicrobial agents that are applied to inanimate object (e.g. floors) 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) Antibiotics come from nature and we can modify them to improve stability and activity. Microorganisms use these antibiotics to compete with each other in a specific niche, sometimes developing resistance. Alexander Fleming (1881-1955) He discovered penicillin in 1928, which was produced from Penicillin notatum. He found that colonies of Staphlococci were not able to grow around a contaminating mold. He was rewarded the Nobel Prize as a result of this discovery. Antibiotics Antibiotics represent our most effective therapeutic against bacterial infection. The availability of antibiotics enables cancer chemotherapy, organ transplantation, and all invasive surgeries. Antibiotic mortality rate is much lower than that of the pre- antibiotic mortality rate  with resistance, we might be moving to the post- antibiotic resistant era. There are two major problems: 1. Diminished interest from pharmaceutical companies to develop new antibiotics  companies are driven to make money, and it is a huge venture to make antibiotics (15-20 years; lots of money). Every time a new antibiotic is introduced in the clinic, the body usually develops resistance right away (most drugs fail, so its just unfeasible). 2. Bacterial resistance to antibiotics always happens Antimicrobial discovery has significantly slowed down because immediate resistance is a huge problem. The 1940-50’s was the golden era for antibiotics. Antibiotic resistance is ancient Antibiotics and antibiotic resistance has been around for a very long time in nature, far before the use of antibiotics in a clinical setting  now we are selecting for a resistant organism. Ancient DNA from frozen permafrost (~30,000 years old) from the Yukon has found antibiotic resistance genes. People used a technique to sequence all the genetic material that you can find in the soil (doesn’t involve culturing). They were able to clone a bank of resistant genes to confirm resistance, so now we are selecting from it. Note: Through air traffic, resistant-selected phenotypes can go global. How do antibiotics work? Antibiotics either kill bacteria, or stop them from growing (not all antibiotics kill bacteria). For bacteriostatic antibiotics, the immune system must take over to kill the bacteria. Measuring Antibiotic Activity The minimum inhibitory concentration (MIC) measures how active the antibiotic is for a particular organism. MIC = lowest concentration of agent that inhibits growth. There are two methods: 1. Old-school method involves a series of culture tubes with varying concentration of agent, where you increase the concentration of antibiotic to see what concentration kills the culture  the lower the MIC, the more potent the antibiotic is 2. Newer method involves antibiotic strips placed on a plate spreaded with bacteria. The strips have different antibiotics (more concentrated on the ends and less in the center  zone of inhibition). This is a faster method. How do antibiotics work? Antibiotics target essential bacterial components, which are unique to bacteria and separate from humans:  Cell wall synthesis  Protein synthesis  DNA/RNA synthesis  Folate synthesis  Cell membrane alteration B-Lactam Antibiotics Penicillin  Contains a “B-lactam ring”  Function to inhibit cell wall synthesis in bacteria  B-lactams bind the bacterial “penicillin-binding proteins” (PBP)  PBPs are transpeptidases  No peptide cross-links = weak cell wall = cell death  But some bacteria can produce B-lactamase (an enzyme that destroys the ring and thus the antibiotic)  B-lactamase producing bacteria are resistant to antibiotics Methicillin  Contains a “B-lactam ring”  Chemically modified penicillin (cant be cleaved by B-lactamases)  But some bacteria can produce a different PBP (e.g. PBP2a, genetically encoded by mec)  PBP2a doesn’t bind methicillin (or other B-lactams)  bacteria are resistant Bacterial Cell Wall Synthesis Transpeptidase is responsible for cell wall synthesis, and B-lactams are antibiotics that inhibit it such that bacteria will not be able to produce a cell wall and die. Bacteria contain B-lactamase, which inhibits B-lactams, thus disallowing it from inhibiting transpeptidase (PBP). Methicillin also inhibits transpeptidase and is resistant to B-lactamase. Bacteria are able to overcome this again by producing a different PBP (PBP2a) such that penicillin and methicillin can’t bind. Vancomycin Vancomycin inhibits cell wall synthesis in Gram positives  often a drug of “last resort” (e.g. HA-MRSA). It is a glycopeptide antibiotic that targets G bacteria (cant get through the outer membrane in G ). 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  resistance is encoded by the van genes. Protein Synthesis Inhibitors Eukaryotes contain 80S (40S+60S) ribosomes, and bacteria contain 70S (30S+50S) ribosomes. Many antibiotics target bacterial ribosomes and block translation.  30S inhibitors (e.g. Tetracycline, Kanamycin)  50S inhibitors (e.g. Erythromycin, Chloramphenicol) Folic acid synthesis inhibitors Folic acid is a vitamin (B9) for humans. Bacteria need folic acid for thymidine synthesis, and they can’t absorb folic acid so they must synthesize their own. Inhibition of folic acid synthesis blocks DNA replication. DNA/RNA synthesis inhibitors Fluoroquinolones: interfere with DNA gyrase needed for supercoiling of DNA Rifampicin: inhibits bacterial RNA polymerase Cell Membrane Alteration
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