BIOL 251 - Ch. 14 Study Points

What are antibiotics and how do they work?

What are antibiotics and how do they work?

Medications used to treat bacterial infections

Bind to cellular component or enzyme and inhibit an essential process

Difference among antibiotics, antifungals, and antivirals

Antibiotics - target bacteria

Antifungals - target fungi

Antivirals - target to disrupt viral cycle

Why are antibiotics effective against bacteria but not effective for other types of microbes?

Only target specific sites or enzymes that are present in bacteria but not other types of microbes

Start of antimicrobial medications

Use of plants, fungi, and other natural products have been used by humans for their medicinal properties

Many plants contain active compounds with medicinal benefits

Ehrlich

Played an important role in the discovery of Compound 606 - antimicrobial agent used to treat syphilis (Treponema pallidum)

Marketed as Salvarsan

First recorded case of antimicrobial use

Prontosil

Used to treat Strep and Staph infections in animal

The actual active ingredient was sulfanilamide - became first sulfa drug

First synthetic antimicrobial created - served as foundation of chemical development of a family of sulfa drugs

Fleming

Credited with discovery of antibiotics

Identified that compounds from Penicillium were toxic to Staph

Penicillin - first natural antibiotic

Received Nobel Prize

Florey and Chain

Scaled up production of penicillin

Showed efficacy of it as well

Received Nobel Prizes

Hodgkins

Determined the structure of penicillin using x-ray crystallography

Led to development of semisynthetic antibiotics

Waksman

Discovered actinomycin, streptomycin, and neomycin - isolated from fungi and Actinobacteria

Many current antibiotics are still of microbial origin

What are sources of natural antibiotics?

Bacteria - Streptomyces are the source of ~1/2 of current antibiotics; Bacillus

Mold - Cephalosporium, Penicillium

Natural antibiotics

Antibiotics that are naturally made from microbes or fungi

What are some examples of natural antibioitics?

Penicillin, Cephalosporins, Streptomycin, Erythromycin, Lincomycin, Tetracycline

Semisynthetic antibiotics

Antibiotics that are derived from microbes or fungi but are modified to fight against inhibitory characteristics of resistant microbes or increase spectrum of the bacteria they effect

What are some examples of semisynthetic antibiotics?

Penicillin V, Amoxicillin, Carbapenems, Azithromycin

Synthetic antibiotics

Completely manmade antibiotics

What are some examples of synthetic antibiotics?

Sulfonamides

What are some examples of penicillins?

Penicillin G, Penicillin V, Ampicillin, Methicillin

Penicillin G

Penicillin that kills Gram + bacteria

Penicillin V

Penicillin that kills Gram + bacteria

Modified to be acid stable - can now be available in pill form

Ampicillin

Penicillin that kills Gram + and - bacteria

Methicillin

Penicillin that’s effective against penicllin-resistant bacteria

What are the key features of antibiotics?

Bacteriostatic/bactericidal

Spectrum of activity - broad/narrow

Target features that are unique to bacteria

Dosage - optimum dosage will minimize the risk of side effects while still achieving clinical cure

Route of administration

Tissue distribution

Metabolism and excretion - half-life

Bacteriostatic antibiotics

Chemicals that inhibit bacterial growth

Doesn’t directly kill the bacteria

Lowers workload that the immune system has to do and gives it an edge

Bactericidal antibiotics

Chemicals that kill bacteria

Inhibit or disrupt a vital cell function

Broad spectrum antibiotics

Antibiotics that affect a wide range of bacterial pathogens

Disruptive to normal microbiota - can result in superinfection

How are broad spectrum antibiotics used for treatment?

Treatment for acute life-threatening diseases - used if causative agent is unknown

Patient can be initially put on broad spectrum antibiotics then transition to narrow spectrum

Narrow spectrum antibiotics

Antibioitcs that affect a limited range of bacteria

Less disruptive to microbiome

How are narrow spectrum antibiotics used for treatment?

Used when the causative agent is known

What are the specific targets of antibiotics?

Cell wall

Plasma membrane

Ribosomes

Metabolic pathways

DNA synthesis

RNA synthesis

What are the different categories of beta-lactam drugs?

Penicillin

Cephalosporin

Monobactam

Carbapenem

Beta-lactam antibiotics

Inhibit cell wall synthesis

Only effective against actively growing cells

Contain beta-lactam rings

Competitively inhibit penicillin-binding proteins (PBPs)

PBPs - catalyzes formation of peptide bridges between adjacent glycan strands

Spectrums of penicillins

Broad spectrum - act against Gram +/-; inactivated by many beta-lactamases

Combination (Augmentin) - Amoxicillin includes beta-lactamase inhibitor clavulanic acid

Cephalosporins

Beta-lactam drug derived from Cephalosporium

5 generations - 5th generation effective against MRSA

Broader spectrum than penicillins and more active against Gram -

More resistant to inactivation by beta-lactamases

Carbapenems

Beta-lactam drugs from Streptomyces

Effective against both Gram +/-

Many synthetics

Not inactivated by beta-lactamases

Monobactams

Beta-lactam drug resistant to beta-lactamases

Narrow spectrum - Gram -

What are the desirable features of semisynthetic antibiotics?

Increased resistance to antibiotic inactivators

Longer half-lives

Less side effects

Broader spectrum

Protein synthesis inhibitors

Aminoglycosides

Tetracyclines

Macrolides

Chloramphenicol

Lincosamides

Oxazolidinodes

Streptogramins

Aminoglycosides

Protein synthesis inhibitor

Bactericidal

Streptomycin

Tetracyclines

Protein synthesis inhibitor

Bacteriostatic, broad spectrum, longer half-life

Doxycycline, tigecycline

Macrolides

Protein synthesis inhibitors

Bacteriostatic, broad spectrum

Azithromycin (Zpack) - long half-life, 68hrs, better patient compliance

Lincosamides

Protein synthesis inhibitor

Strep and Staph infections

Linocomycin, Clindamycin

Oxazolidinodes

Protein synthesis inhibitor

Good for vancomycin resistance

Streptogramins

Protein synthesis inhibitor

Treat antibiotic resistant Gram +

Nucleic acid inhibitors

Flouroquinonlones

Rifamycins

Fluoroquinolones

Nucleic acid inhibitor

Inhibits topoisomerase and DNA gyrase

Cirpofloxacin, levofloxacin

Effective against Gram +/-

Rifamycins

Nucleic acid inhibitor

Blocks initiation of transcription

Rifampin

Metabolic pathway inhibitors

Folate inhibitors

Sulfonamides

Folate inhibitors

Metabolic pathway inhibitors

Most useful

Folate is needed for nucleotide synthesis - lethal if pathway is inhibited

Sulfonamides

Metabolic pathway inhibitor

Interfere with tetrahydrofolic acid synthesis

Cell membrane disruptors

Polymixin B

Izoniazid

Polymixin B

Cell membrane disruptor

Bind to lipopolysaccharide layer

Makes cell membrane leaky

What are some tests that evaluate antibiotic susceptibility/sensitivity?

Kirby-Bauer disc diffusion test

Minimum inhibitory concentration (MIC), minimum bacterial concentration (MBC)

E-test

Kirby-Bauer disc diffusion test

Determine susceptibility of bacterial strain to antibiotics

Measure zone of inhibition to determine whether strain is susceptible, intermediate, or resistant

MIC + MBC

MIC - lowest concentration that prevents growth in vitro, pick serial dilutions that are clear (low turbidity)

MBC - lowest concentration that kills 99.9% of starting inoculum of cells in vitro, plate count of MICs with no visible growth

E-test

Combo of Kirby-Bauer disk diffusion test and dilution methods

Plastic strips contain gradient of antibacterial

Rate of drug diffusion directly related to concentration - intersection = MIC

Intrinsic resistance

Naturally occurring and not result of exposure to clinical antibiotic

More likely due to chromosomal genes rather than mobile genetic elements

Protection against naturally-occurring antibiotic production

Acquired resistance

Resistance due to the repeated presence of clinical antibiotics

Transferred thru horizontal gene transfer and conjugative transfer of R plasmids

What are the mechanisms of acquired resistance?

Drug-inactivating or modifying enzymes

Decreased uptake of drug

Increased elimination of drug - increased expression of efflux pumps

Alteration/modification of target molecule - target overproduction, target mimicry

What are factors that contribute to the rise of antibiotic resistance?

Increasing use, misuse, and overuse

Subtherapeutic dosing

Patient noncompliance

What are some important antibiotic resistant strains?

Vancomycin resistant Enterococcus (VRE)

Superbugs - multidrug-resistant microbes

Gram - pathogens that produce extended spectrum beta-lactamase

Carbapenem resistant Enterobacteriaceae/Gram - bacteria

Streptococcus pneumoniae

Mycobacterium tuberculosis

MRSA

VRSA

VISA

How can antibiotic resistance be reduced/prevented?

Physician responsibility - better diagnosis, appropriate treatment

Patient responsibility - following dosage

Educating public

Global impact