2/10/2016 Antimicrobial drugs act by inhibiting or Microbes Food interfering with the growth of microbes. Microbiology Antimicrobial drugs act within the host without damaging the host. AN INTRODUCTION Invisible Invaders Antibiotics are one of the most important Amazing Allies discoveries of modern medicine. Resistance to antibiotics poses a"major global threat"to public health according to WHO. Antimicrobial Drugs iborEgomay The Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs Antibiotic:a substance produced by a microbe that,in small amounts,inhibits ·caRe味ofn2 gthor another microbe Broad-spectrum antibiotics:affect a broad range of gram-positive or gram-negative bacteria Antimicrobial drugs:synthetic substances that interfere with the growth of microbes 1
2/10/2016 1 Invisible Invaders Amazing Allies Antimicrobial Drugs • Antimicrobial drugs act by inhibiting or interfering with the growth of microbes. • Antimicrobial drugs act within the host without damaging the host. • Antibiotics are one of the most important discoveries of modern medicine. • Resistance to antibiotics poses a "major global threat" to public health according to WHO. Pseudomonas aeruginosa resistant to many antibiotics • Antibiotic: a substance produced by a microbe that, in small amounts, inhibits anoth i b er microbe • Antimicrobial drugs: synthetic substances that interfere with the growth of microbes The Spectrum of Activity of Antibiotics and Other Antimicrobial Drugs • Narrow spectrum of microbial activity: drugs that affect a narrow range of microbial types • B d roa -spect tibi ti trum antibiotics: aff t b d f ffect a broad range of gram-positive or gram-negative bacteria
2/10/2016 The Action of Antimicrobial Drugs Five Major Targets of Antibacterial Drugs Antimicrobial drugs target essential functions of the microbe ·Bactericidal -Kill microbes directly ·Bacteriostatic -Prevent microbes from growing -Host's immune system usually kills the pathogen 3. The Action of Antimicrobial Drugs Inhibition of bacterial cell wall synthesis by .Inhibiting cell wall synthesis penicillin -Peptidoglycan is found only in bacterial cell walls. -Penicillins prevent the synthesis of peptidoglycan -Cell wall is weakened and undergoes lysis. lod-shaped bacleriu
2/10/2016 2 The Action of Antimicrobial Drugs • Bactericidal – Kill microbes directly • Bacteriostatic – Prevent microbes from growing – Host’s immune system usually kills the pathogen Five Major Targets of Antibacterial Drugs Antimicrobial drugs target essential functions of the microbe. The Action of Antimicrobial Drugs • Inhibiting cell wall synthesis – Peptidoglycan is found only in bacterial cell walls. – Penicillins prevent the synthesis of peptidoglycan – Cell wall is weakened and undergoes lysis. Inhibition of bacterial cell wall synthesis by penicillin
2/10/2016 The Action of Antimicrobial Drugs Protein synthesis Inhibiting protein synthesis Protein -Target bacterial 705 ribosomes -Eukaryotes have 80S ribosomes -Difference in ribosome structure accounts for selective toxicity -However,mitochondria have 70S ribosomes so some toxicity may occur -Chloramphenicol,erythromycin, mRNA 3 streptomycin,tetracyclines (a)Three-d ional detail ofth subunit portions of the 705 prokaryotic Inhibition of protein synthesis by antibiotics. The Action of Antimicrobial Drugs Growing polypeptide Injuring the plasma membrane -Polypeptide antibiotics change membrane permeability -Antifungal drugs combine with membrane -Protein synthesis site sterols ·Injury to the plasma Direction of ribosome movement st cell reptomycin Tetracyclines Interfere with on mRNA to be Translation antifungal drugs
2/10/2016 3 The Action of Antimicrobial Drugs • Inhibiting protein synthesis – Target bacterial 70S ribosomes – Eukaryotes have 80S ribosomes – Difference in ribosome structure accounts for selective toxicity – However, mitochondria have 70S ribosomes so t i it some toxicity may occur – Chloramphenicol, erythromycin, streptomycin, tetracyclines Protein synthesis Protein synthesis site Growing polypeptide Tunnel 5' 50S 30S mRNA 3' Three-dimensional detail of the protein synthesis site showing the 30S and 50S subunit portions of the 70S prokaryotic ribosome Inhibition of protein synthesis by antibiotics. Growing polypeptide 50S Chloramphenicol Binds to 50S portion and inhibits formation of tid b d Messenger RNA 50S portion tRNA Protein synthesis site peptide bond RNA Streptomycin Changes shape of 30S portion, causing code on mRNA to be read incorrectly 70S prokaryotic ribosome Translation 30S portion Direction of ribosome movement Tetracyclines Interfere with attachment of tRNA to mRNA– ribosome complex The Action of Antimicrobial Drugs • Injuring the plasma membrane – Polypeptide antibiotics change membrane p m bilit permeability – Antifungal drugs combine with membrane sterols • Injury to the plasma membrane of a yeast cell caused by an antifungal drug. • Cell releases its cytoplasmic contents as the plasma membrane is disrupted by antifungal drugs
2/10/2016 The Action of Antimicrobial Drugs Competitive Inhibition of an Enzyme Inhibiting nucleic acid synthesis PABA-substrate for an enzymatic reaction in the synthesis of folic acid,a vitamin that functions as a coenzyme in the -Interfere with DNA replication and synthesis of nucleic acids transcription -Some interfere with mammalian DNA and RNA NH2 as well. HO Inhibiting the synthesis of essential 0S0 metabolites -Antimetabolites compete with normal rates for an enzyme cpparg-minobenoie NH2 NH2 hemef nucleic Sulfanilamide PABA Susceptibility to Antimicrobials Resistance to Antimicrobial Drugs Different in different species and Persister cells:subpopulation of microbes with strains C characteristics that allow their s Changes with time,even during therapy en exposed to antibiotic witho undergoing genetic change:type of dormant cell Several tests are used to indicate an Superbugs:bacteria that are resistant to large effective therapeutic agent numbers of antibiofics -Broth dilution tests Resistance genes are often spread horizontally -Disk-Diffusion Method among bacteria on plasmids or transposons via conjugation or transduction -E-test
2/10/2016 4 The Action of Antimicrobial Drugs • Inhibiting nucleic acid synthesis – Interfere with DNA replication and transcr transcr pt on i i – Some interfere with mammalian DNA and RNA as well. • Inhibiting the synthesis of essential metabolites – Antimetabolites compete with normal substrates for an enzyme • Sulfanilamide competes with para-aminobenzoic acid (PABA) • stops synthesis of folic acid, a vitamin that functions as a coenzyme in the synthesis of nucleic acids Competitive Inhibition of an Enzyme PABA - substrate for an enzymatic reaction in the synthesis of folic acid, a vitamin that functions as a coenzyme in the synthesis of nucleic acids Susceptibility to Antimicrobials • Different in different species and stra ns i • Changes with time, even during therapy • Several tests are used to indicate an effective therapeutic agent – B th dil ti t sts Broth dilution tests – Disk-Diffusion Method – E-test Resistance to Antimicrobial Drugs • Persister cells: subpopulation of microbes with genetic characteristics that allow their survival when exposed to an antibiotic without undergoing genetic change; type of dormant cell • Superbugs: bacteria that are resistant to large numbers of antibiotics • Resistance genes are often spread horizontally among bacteria on plasmids or transposons via conjugation or transduction
2/10/2016 Mechanisms of Resistance Persister-involves a 1.Destruction or inactivation of the drug by metabolic shutdown enzymes not a genetic mutation .Beta-lactamases breakdown penicillin-like drugs 2.Prevention of penetration to the target site within the microbe .Gram-negative porins are altered 3.Alteration of the drug's target site Antibiotic resistance tests .mutations affect drug interaction but not function of the target che lasses-Left most image 4.Rapid efflux (ejection)of the antibiotic 5.Variations of mechanisms of resistance Example mechanisms of antibiotic resistance Rapid development of an antibiotic-resistant 4 2 mutant during antibiotic therapy Antibiotic resistance of bacterial 1 Efux pump Decreased uptak biatic eeded to c 50 40 20 0000C0000MPw4 5 3 7B9011 5
2/10/2016 5 Persister - involves a metabolic shutdown not a genetic mutation A tibi ti i t t t Antibiotic resistance tests Superbugs – resistant to most antibiotic chemical classes – Left most image Mechanisms of Resistance 1. Destruction or inactivation of the drug by enzymes • Beta-lactamases breakdown penicillin-like drugs 2. Prevention of penetration to the target site within the microbe • Gram-negative porins are altered 3. Alteration of the drug's target site • mutations affect drug interaction but not function of the target 4. Rapid efflux (ejection) of the antibiotic 5. Variations of mechanisms of resistance Example mechanisms of antibiotic resistance Rapid development of an antibiotic-resistant mutant during antibiotic therapy Initiation of antibiotic therapy Antibiotic resistance of bacterial population measured by amount of antibiotic needed to control growth Bacteria count
2/10/2016 Antibiotic Misuse Misuse of antibiotics has selected for a host of penicillin-fast organisms is bred out... resistance mutants leading to antibiotic In such cases,the thoughtless person playing with resistance in bacterial strains penicillin is morally responsible for the death of ·Misuse includes: the man who finally succumbs to infection with the penicillin- -Using outdated or weakened antibiotics -Using antibiotics for the common cold and resistant organism.I hope this other inappropriate conditions evil can be averted. -Using antibiotics in animal feed -Failing to complete the prescribed regimen -Using someone else's leftover prescription Antibiotics have been sold without CDC estimates for unnecessary antibiotic prescriptions for many decades in much of prescriptions in the United States the world. Unnecessary Antibiotic Prescriptions Rural Bangladesh-8%of antibiotics are Preseriptar间 prescribed by a physician 80% N 6
2/10/2016 6 Antibiotic Misuse • Misuse of antibiotics has selected for resistance mutants leading to antibiotic resi i b i l i istance in bacterial strains • Misuse includes: – Using outdated or weakened antibiotics – Using antibiotics for the common cold and other inapp p ro riate conditions – Using antibiotics in animal feed – Failing to complete the prescribed regimen – Using someone else's leftover prescription • Antibiotics have been sold without prescriptions for many decades in much of the world. • Rural Bangladesh – 8% of antibiotics are prescribed by a physician CDC estimates for unnecessary antibiotic prescriptions in the United States
2/10/2016 Clinical Focus:Antibiotics in Animal Feed Linked to Humen Disease At least 70%of antibiotics produced in the US are NOT used to treat disease but are used in animal feeds to promoter growth. FQ for In 2006,European Union banned the use of antibiotics as a growth enhancer In2012.FDA banned use of one class of antibiotics in feed In 2013.FDA promoted a voluntary plan for industry to phase out use of some antibiotics October 10.2015,the first US state to ban use of antibiotics as growth enhancers California governor signs bill to require a veterinarian's prescription for therapeutic antibiotic uses in livestock and ban other uses. f8oe3opgeiCes5amayefmeU25mion Antibiotic Cost and Prevention Fluoroquinolone(FQ)-resistance in C.jejuni emerged in 1990s. Developing new drugs is a costly process May result in drugs that are too costly for many to afford chicken. Strategies to prevent antibiotic resistance: However,patients infected with the FQ- -Finish the full antibiotic prescription resistant C.jejuni had not taken the antibiotic -Never use leftover antibiotics to treat new illnesses -Avoid unnecessary prescriptions -Ensure the choice and dose are appropriate In 2005,the use of FQ in chicken feed was -Avoid broad-spectrum antibiotics if possible banned in hopes of reducing FQ resistance. >
2/10/2016 7 At least 70% of antibiotics produced in the US are NOT used to treat disease but are used in animal feeds to promoter growth. • In 2006, p Euro ean Union banned the use of antibiotics as a growth enhancer • In 2012, FDA banned use of one class of antibiotics in feed • In 2013, FDA promoted a voluntary plan for industry to phase out use of some antibiotics • October 10, 2015, the first US state to ban use of antibiotics as growth enhancers California governor signs bill to require a veterinarian’s prescription for therapeutic antibiotic uses in livestock and ban other uses. Clinical Focus: Antibiotics in Animal Feed Linked to Human Disease FQ for humans FQ for poultry FQ for poultry discontinued obacter 25 30 Flouroquinolone-resistant Campylobacter jejuni in the United States, 1986–2008. Q-resistant Campylob 101520 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 Year Percent FQ 0 5 0 • Campylobacter jejuni causes over 2.5 million foodborne illness annually in the US. • Fluoroquinolone (FQ)-resistance in C. jejuni emerged in 1990s. • Emergence corresponded with presence of FQresistant C. jejuni in grocery store-purchased chicken. • However, patients infected with the FQresistant C. jejuni had not taken the antibiotic prior to their illness and had not traveled out of the United States. • In 2005, the use of FQ in chicken feed was banned in hopes of reducing FQ resistance. Antibiotic Cost and Prevention • Developing new drugs is a costly process • May result in drugs that are too costly for many to afford • Strategies to prevent antibiotic resistance: – Finish the full antibiotic prescription – Never use leftover antibiotics to treat new illnesses – Avoid unnecessary prescriptions – Ensure the choice and dose are appropriate – Avoid broad-spectrum antibiotics if possible
2/10/2016 New antibiotics approved by the Industry's dilemma:new antibiotics are in demand but the US Food and Drug Administration returns are often low and take years to be realized 15 12 -s.coom 198g161978807098 andand Antibiotic Safety Future of Chemotherapeutic Agents Therapeutic index:risk Antibiotic Safety versus benefit Target virulence factors Reactions of antibiotics Sequester iron,which feeds pathogens with other drugs ·Damage to organs out of5 Antimicrobial peptides produced by ·Risk to the fetus various organisms Allergies to antibiotics ·Phage therapy Bacteriocins:antimicrobial peptides produced by bacteria ·Natural products
2/10/2016 8 Industry's dilemma: new antibiotics are in demand but the returns are often low and take years to be realized Antibiotic Safety • Therapeutic index: risk versus benefit • Reactions of antibiotics with other drugs • Damage to organs • Risk to the fetus • Allergies to antibiotics Future of Chemotherapeutic Agents • Target virulence factors • Sequester iron, which feeds pathogens • Antimicrobial peptides produced by various organisms • Phage therapy • B i i i i bi l id Bacteriocins: antimicrobial peptides produced by bacteria • Natural products
2/10/2016 TEIXOBACTIN-A NEW ANTIBIOTIC ⊙ New methods for discovery
2/10/2016 9 New methods for discovery