Reading_Antibiotics_1 - Antibiotics, Resistance &...

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Unformatted text preview: Antibiotics, Resistance & Our Most Feared Pathogens Antibiotics These are compounds that are selectively toxic to pathogenic microbes but not host cells. In this lecture, we will focus exclusively on antibiotics directed against pathogenic bacteria. Effect on cells Textbook Reading Pages 186-189, Section 7.3 The points to be remembered from this text: Be able to explain the difference between bacteriostatic and bacteriolytic antibiotics. For the purposes of this class, we will use only these two terms. Know how the MIC is determined and how it is used to determine the antibiotic sensitivity of a bacterium. Consider what are the limitations of this technique. Synthetic Versus Natural Antibiotics Natural antibiotics are produced by biological systems (e.g. bacteria and fungi), with most clinically used antibiotics being produced by the Actinomyces group of bacteria. Synthetic antibiotics are not produced biologically but are designed and discovered in the laboratory. Semisynthetic antibiotics are natural antibiotics that have been modified in the laboratory. In general, synthetic and natural (including semisynthetic) antibiotics have different biological targets, and bacteria have developed different mechanisms to resist synthetic versus natural antibiotics. Targets of Antibiotics The antibiotics with the greatest clinical use target one of four different biological functions in bacteria cells. Cell wall biosynthesis ß-lactam antibiotics and the glycopeptides, vancomycin, inhibit transpeptidation and are used to treat human infections. Moenomycin inhibits transglycosylation, and is used as a growth promoter in animal feed. Textbook Reading Pages 194, “Cell Wall Synthesis” The points to be remembered from this text: Know that ß-lactam antibiotics are the major class of antibiotics in clinical use. These antibiotics are derivatives of the penicillins and cephalosporins. Know how ß-lactam antibiotics inhibit cell-wall biosynthesis. Bacterial ribosomes Aminoglycosides, macrolides, and tetracyclines are the three major classes of antibiotics that work by inhibiting the bacterial ribosome. For example, the macrolide antibiotic, 1 erythromycin, inhibits the ribosome by binding the 23S rRNA. A pair of antibiotics that are cyclic peptidolactones work synergistically to inhibit the 23S rRNA. The pair has the name Synercid, and inhibits vancomycin resistant enterococci. (Optional reading = “Protein Synthesis” 195-196). DNA replication and repair Quinolones are synthetic antibiotics that inhibit DNA gyrase. DNA gyrase introduces negative supercoils in double stranded circular DNA. This activity is thought to be important for controlling DNA topology during DNA replication, recombination, and transcription. The fluoroquinolones are active against Gram-positive and Gram-negative bacteria. Folate biosynthesis Folate is required for the synthesis of nucleotides for DNA synthesis. Unlike our cells, bacteria synthesize folate. Sulfa drugs and trimethroprim, both of which inhibit folate biosynthesis, are used in combination to treat urinary tract infections and Pneumocystis carinii infections of AIDS patients. Antibiotic Resistance Bacteria that make antibiotics must have a mechanism to resist their action; antibiotic production would be a suicidal act. Scientists believe antibiotics and resistance co-evolved. Their expression is even co-regulated in some bacterial species. Likewise, the microbial neighbors, against which they are waging war with the antibiotics, have had millions of years and strong selective pressure to develop resistance. Is it any surprise then that clinically relevant forms of antibiotic resistance developed within just a short time of the introduction of antibiotics into medicinal use? Consequences of antibiotic resistance 40% of hospital acquired Staphylococcus aureus and 50% of hospital-acquired Staphylococcus epidermidis infections are methicillin-resistant. In blood-borne infections by these bacteria, the mortality rate is 25 to 63%. Enterococci account for 12% of hospital infections; 15% of these infections are vancomycin resistant. Mortality rates for infection by vancomycin-resistant entrococci are 42 to 81%. Why do antibiotic resistant mutants develop so readily? DNA polymerase will make an error every 1 in 107 bases replicated. In a 3 x 106 bp genome, containing 3000 genes, that is 0.3 errors per generation. If there are 1011 bacteria in a population, as can be the case in a bloodstream infection. Then there may be 1000 mutants. If the mutations are randomly distributed, then 1 out of 3 genes has a mutation. If one provides resistance to an antibiotic, then the mutant will grow while his neighbors die. Now, imagine 100 people with a similar infection and identical antibiotic treatment, then 100,000 mutants are present in the total population. Each gene in the genome will have had >3 different mutations. 2 The second reason antibiotic resistance develops so readily is that the bacteria that developed antibiotics also simultaneously developed ways to avoid destruction by these antibiotics. These antibiotic resistance mechanisms can then be transferred to other bacterial species by horizontal gene transfer. Innate resistance - the outer membrane Some antibiotics only work on Gram-positive bacteria. The Gram-negative bacteria are protected by their outer membrane (OM). Glycopeptides are too large to diffuse through the pores of the OM. Due to differences in the outer membrane, different species of Gram-negative bacteria can have different sensitivities to antibiotics. For example, E. coli is sensitive to ampicillin, but Pseudomonas aeruginosa is resistant, apparently due to the smaller pore size in the OM of P. aeruginosa. Forming Biofilms Biofilms are surface-adhered, muticellular form of bacterial growth in which the bacteria are encased in an extracellular matrix. This matrix is typically composed of polysaccharides. Biofilms are particularly prone to form in the medical setting on forgein material implanted in the body, such as IV tubes and catheters. While bacteria are present in biofilms, they are significantly more resistant to antibiotics than when they are not in a biofilm. The mechanism by which biofilm bacteria resist antibiotics is not well understood. Antibiotic export Antibiotics are produced intracellularly where there is ATP for synthesis. After synthesis, these antibiotic producing bacteria need a mechanism to export the antibiotic. Thus, most antibiotic producing bacteria encode an efflux pump (i.e. a transporter that exports). Modifying the Substrate Another mechanism of resistance is modification of the substrate targeted by the antibiotic such that the antibiotic can not bind. For example, erythromycin resistance can be conferred by methylation of 23S rRNA. This methylation prevents binding of erythromycin to the ribosome. Antibiotic modification The best known example of this mechanism of resistance is the cleavage and inactivation of ß-lactam antibiotics by the enzyme ß-lactamase. Genetically acquiring antibiotic resistance Cells can become resistant to antibiotics by either acquired resistance mechanisms from other bacteria or through mutation of the gene encoding the protein targeted by the antibiotic. For example, resistance to DNA gyrase inhibitors occurs through mutations in the gene encoding DNA gyrase that prevent antibiotic binding but retains catalytic activity. Acquiring mutations is the most common mechanism of developing resistance to antibiotics. 3 Combating Antibiotic Resistance Variants of existing antibiotics Modify side-chains of ß-lactam antibiotics to resist the action of ß-lactamases. New Antibiotics Inhibit resistance enzymes Clavulanic acid inhibits ß-lactamase, which degrades the ß-lactam ring of the ß-lactam antibiotics. Limit the time to development of resistance Limit unnecessary prescriptions. Significantly reduce agricultural use. “There are many problems with antimicrobial-use practices in the food-animal industry, including largescale use of low-dose, long-duration antimicrobials for non-therapeutic purposes; mass antimicrobial administration, known as metaphylaxis, to treat a small number of sick animals; use of antimicrobials in the same class as those used in humans; and a lack of adequate regulation of antimicrobial use. Most antimicrobial administration in food animals is not for treatment, or even prophylaxis, of infection; on the contrary, it is for growth-promotion purposes. Therefore, antimicrobials are administered to herds of animals at subtherapeutic doses, often for weeks to months, providing the perfect setting for selection of drug-resistant bacteria. … Antimicrobial resistance has been on the rise in nontyphoidal salmonellae around the world. The Enter-net surveillance system in Europe found that, of 27,000 cases of human salmonellosis in 2000, nearly 40% were resistant to at least one antimicrobial agent, with 18% being resistant to 4 or more unrelated antimicrobials. In developed countries, resistance seems to be largely a consequence of the extensive use of antimicrobials in food animals to improve growth rate. For instance, Denmark and Taiwan have seen significant increases in quinolone-resistant Salmonella enterica species in humans in the setting of growing fluoroquinolone use in food animals.” Nature Reviews Microbiology Vol. 4 Pages 39-45 2006. 4 ...
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