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Chapter 20: Antimicrobial Drugs Antimicrobial Drugs • Chemotherapy The use of drugs to treat a disease • Antimicrobial drugs Interfere with the growth of microbes within a host • Antibiotic: Substance produced by a microbe that, in small amounts, inhibits another microbe Table 20.1 www.textbookofbacteriology.net • 1928 – Fleming discovered penicillin, produced by Penicillium (mold) • First clinical trials in early 1940s Figure 20.1 Broad-spectrum antibiotics: those that affect a broad range of gram-positive and/or gram-negative bacteria Table 20.2 Antimicrobial Drugs: Selective Toxicity • Selective toxicity: property of a drug that allows it to kill microbes without damaging the host cells ─ Takes advantage of differences in cell structure and metabolism between the microbe and host cells ─ Antibacterials: target prokaryotic structures ◦ Penicillin prevents proper synthesis of peptidoglycan The Action of Antimicrobial Drugs • Bactericidal: causes death of bacteria • Bacteriostatic: prevents growth of bacteria Targets of Antimicrobial Drugs Figure 20.2 Targets of Antimicrobial Drugs: Cell wall synthesis • Penicillin: weakens bacterial cell walls by inhibiting the crosslinking of peptidoglycan ─ Peptidoglycan is found only in bacterial cell walls ─ Bactericidal (must be actively growing) Targets of Antimicrobial Drugs: Cell Wall Synthesis Penicillins ─ Natural penicillins ◦ Isolated from Penicillium mold ◦ Narrow spectrum of activity ◦ Susceptibility to penicillinases (or β–lactamases) ─ Semisynthetic penicillins ◦ Chemically add new side chains to nucleus in attempt to − reduce susceptibility to penicillinase − extend their spectrum of activity Targets of Antimicrobial Drugs: Cell Wall Synthesis Penicillins ─ Semisynthetic penicillinase-resistant penicillins ◦ Methicillin was the first −Resistant strains of staphylococci have become prevalent: MRSA (methicillin-resistant Staphylococcus aureus) Targets of Antimicrobial Drugs: Protein Synthesis • Exploit 70S ribosomes of prokaryotic cells ─ Eukaryotic (host) cells: 80S ribosomes ◦ Host side effects due to mitochondrial toxicity (mitochondria: 70S) Figure 20.4 Targets of Antimicrobial Drugs: Protein Synthesis • Tetracyclines ─ Broad spectrum of activity ─ Inhibit the association of tRNAs with the 70S ribosome ─ Prevent the addition of amino acids to the growing protein chain ─ Bacteriostatic http://student.ccbcmd.edu/courses/bio141/lecguide/unit2/control/i mages/tetres.gif Other Targets of Antimicrobial Drugs • Plasma membranes ─ Drugs increase membrane permeability • Nucleic acid synthesis ─ May affect mammalian nucleic acid synthesis as well • Essential metabolite synthesis ─ Competitive inhibitors that prevent production of metabolites that are essential for growth/survival of the microbe Testing effectiveness of antibiotics on bacteria: Disk-Diffusion Test • Zone of inhibition diameter reflects susceptibility of test organism to antibiotic drug Figure 20.17 Effects of Combinations of Drugs • Antagonism: the effect of two drugs together is less than the effect of either alone • Synergism: the effect of two drugs together is greater than the effect of either alone ─ i.e. Polymyxin (membrane-disrupting drug) makes it easier for streptomycin to enter the cell Effects of Combinations of Drugs Figure 20.22 Antibiotic Resistance • Cellular mechanisms of antibiotic resistance: 1. Prevention of penetration of drug into cell 2. Alteration of drug's target site (Mutation) 3. Enzymatic destruction of drug 4. Rapid ejection of the drug (Efflux) http://www.fda.gov/cvm/antiresistvideo.htm • Resistance genes are often on plasmids that can be transferred between bacteria ─ 1968: 12,500 Guatemalans died of Shigella diarrhea ◦ This strain contained a plasmid with resistance to four antibiotics Emergence of Antibiotic-resistant mutant bacteria • Antibiotic-resistant bacteria replacing the sensitive population ─ Every time an antibiotic is used, sensitive bacteria are killed, and resistant bacteria may survive and continue to grow (repopulate) ─ Presence of the antibiotic provides selective pressure ◦ Selecting for antibiotic-resistant bacteria ◦ Survival of the fittest Figure 20.20 Infection Antibiotic Administration Appropriate dose/duration Extinction of the whole bacterial population -Sensitive cells die -Resistant cells die Inappropriate dose/duration Evolution of the surviving bacterial population -SELECTIVE PRESSURE -Sensitive cells die -Resistant cells survive, grow MRSA • About half of S. aureus infections in US are resistant to penicillin, methicillin, tetracycline, and erythromycin • Methicillin-resistant Staphylococcus aureus ─ Frequently used to describe S. aureus strains resistant to all penicillins ─ “Quite common” in hospitals ─ Current treatment for MRSA is vancomycin, the last weapon in the arsenal ◦ VRSA was reported in 1997, and is (slowly) on the rise • As more antibiotics are discovered/synthesized, bacteria continue to adapt by developing and sharing antibiotic resistance MRSA infections: small red bumps deep, painful abscesses http://www.mayoclinic.com/images/image_popup/ans7_staph_skin.jpg Antibiotic Resistance • One of the world’s most pressing health problems • Misuse of antibiotics selects for resistant mutants Misuse includes: ─ Using outdated, weakened antibiotics ─ Using someone else's leftover prescription ─ Failure to complete the prescribed regimen ─ Using antibiotics for the common cold and other inappropriate conditions ─ Use of antibiotics in animal feed Each of these applies selective pressure on a microbial population, favoring resistant cells. Acquisition of fluoroquinolone (FQ)-resistant Campylobacter from poultry. • FQ approved for use in poultry in 1995 • FQ use discontinued in 2001 www.cdc.gov/ncidod/EID/vol10no6/04-0403-G.htm Strategies to Reduce Emergence of Antibiotic-resistant bacteria • Prescription of antibiotics only when it will likely benefit the patient • Use an agent with narrow spectrum of activity when possible • Use antibiotics at the proper dose and duration http://www.nearingzero.net/screen_res/nz149.jpg