Openstax microbiology Chapter 14: Antimicrobial Drugs

AMR

Antimicrobial Resistance

Paul Ehrlich

Discovered first cure for syphilis. compound 606

Selective toxicity

selectively finding and destroying pathogens without damaging the host. " magic bullets"

Salvarsan

Paul Ehrlich discovered an arsenic derivative, ___, that was effective against syphilis.

Gerhard Domagk

Prontosil (red dye) that inhibits gram positive species

e.g. streptococcus and staphylococcus

Alexander Fleming

discovered penicillin. penicillum mold produces a substance that kills gram positive bacteria. "penicillin effect"

Howard Florey and Ernst chain

purified penicillin, the first commercial antibiotic to save human lives.

Effective against gonorrhea, meningitis, and diptheria

Selman Waksman

1ST to show vast microbial production capabilities of a group of soil bacteria- ACTINOMYCETES

Coined the word antibiotic and discovered several other antimicrobials

Synthetic Antimicrobial

developed from a chemical not found in nature

Natural antimicrobial

a product of nature/ produced by living organisms most popularly fungi and bacteria

Semisynthetic Antimicrobial

chemically modified derivative of a natural antibiotic

How do you decide to use a bacteriostatic drug over a bacteriocidal drug?

it is dependent upon the type of infection and the age and immune status of the patient

Narrow Spectrum Antimicrobial

Targets on specific subsets of bacterial pathogens

Broad Spectrum Antimicrobial

Targets a wide variety of bacterial pathogens including gram positive and gram negative. It is used frequently as empiric theory to cover many potential pathogens while waiting on results.

Risk of superinfection

1. Normal microbiota keeps opportunistic pathogens in check

2. Broad-spectrum antibiotics kill non-resistant cells

3. Drug resistant pathogens proliferate

What group of antimicrobial are broad spectrum?

Penicillin, sulfonamides, streptomycin, tetracyclines.

What group of antimicrobial are narrow spectrum?

Isoniazid, polymycin, vancomycin, rifampin

Dosage

amount of medication given during a certain time interval. Must be determined carefully to ensure optimum therapeutic drug levels at the site of infection without side effects

Route of administration

method used to introduce a drug into the body. Oral, intramuscular, intravenous, topical

Selective toxicitty

selectively kills or inhibits the growth of microbial targets while causing minimal or no harm to the host.

Why are most antimicrobial drugs antibacterial

Because the prokaryotic cell provides a greater variety of unique targets for selective toxicity

Antimicrobials that attack the cell wall

MOA: inhibit cell wall biosynthesis

Target: penicillin binding proteins- B-lactams

Target: Peptidoglycan sub units- Glycopeptides

Target: Peptidoglycan sub-unit transport- Bacitracin

Antimicrobials that attack the plasma membrane

MOA: disrupt membranes

Target: Lipopolysaccharides- Polymyxins/ lipopeptide

Antimicrobials that attack ribosomes

MOA: inhibit biosynthesis of proteins

Target: 30S- aminoglycosides

Target: 50S -macrolides, chloramphenicol

Antimicrobials that attack DNA and RNA synthesis

MOA: inhibit nucleic acid synthesis

Target: RNA- rifamycin

Target: DNA- fluoroquinolones

Antimicrobials that attack metabolic pathways

MOA: antimetabolics

Target: Folic acid synthesis enzyme- Sulfonamides

Target: Mycolic acid synthesis enzyme- Izoniazid

Penicillin

natural/ semi-synthetic

B-lactam ring within the central structure of the molecule

resistant bacterial species produce b-lactamses to inactivate the molecule, which is why semi-synthetic species have been created

What penicillin-like drugs have a broader spectrum

ampicillin and amoxicillin

Cephalosporins

natural/ semi-synthetic

used against penicillin resistant bacteria or if the patient has a penicillin allergy. Best against MRSA

Vancomycin

natural from actinomycete

glycopeptide- large molecule that binds to the peptide chain of peptidoglycan

Bacitracin

natural from a bacillus subtilus

interferes with transport through membrane. Used to treat skin infections that are gram positive and gram negative

30S antimicrobials

aminoglycoside and tetracydines (broad)

Side effects: discoloration of teeth and liver toxicity

50S antimicrobials

erythromycin, azithromycin.

Chloraphenicol is the first broad spectrum approved by the FDA.

Can treat anything from meningitis to typhoid fever to conjunctivitis

Side effects: gray baby syndrome, anemia, bone marrow suppression

Polymyxins

produced by bacillus polymyxa

increases the membrane permeability of gram negative rods leading to cell death

-detergent-like properties

Rifamycin

inhibits bacterial RNA polymerase activity and binds transcription killing the cell

- narrow spectrum (gram positive and TB)

Flurorquinolones

inhibits the activity of DNA gyrase and blocks replication killing the cell

-Broad spectrum (gram positive and gram negative)

Folic acid synthesis

sulfonamides are structurally similar to PABA and blocks the enzymatic process by competition.

-works because human eat their folic acid instead of synthesizing it

Mycolic acid synthesis

Isoniazid is specific for mycobacteria.

Used to treat TB

Side effects: hepatoxicity, neurotoxicity, hematologic toxicity

What are some anitfungal drugs?

Amphotericin B, Nystatin, and Griseoflavin

Amphotericin B

an antifungal that attacks steroids in the plasma membrane. It focuses on Ergosterol since humans have cholesterol.

Nystatin

changes the cell membrane permeability

-used to treat candida albicans

Griseoflavin

used to treat fungal infections of hair, skin, and nails like worms. it works by interfering with fungal mitosis

What are the anti-protozoan drugs?

Aretmisinin, antimetabolites, and quinolones

Areteminisn

acts as a pro-drugs that is metabolized by the target cell to produce reactive oxygen that then damages that target cell

Antimetabolites

completely inhibits the enzyme in folic acid production

Quinolones

interfere with heme detoxification which a parasite needs to break down hemoblobin into amino acids

Antihelminthic drugs

target: inhibiting micro tubule formation, block neuronal transmission, inhibit ATP production, induce calcium influx, and inhibit RNA synthesis

Viral structure

nucleid acid, protein coat, viral enzymes, and may or may not have a lipid coat

-obligate intracellular pathogens, having to use host cell machinery to replicate

Antiviral drugs

Acyclovir, Amantidine, tamiflu &relenza, azidothymine, ritonavir

Acyclovir

guanosine analog. a nucleoside analog that functions by inhibiting nucleic acid biosynthesis.

1. viral enzymes add a phospahte group to acyclovir

2. human enzymes add two mor phosphate groups making it acyclovir triphosphate

3. During viral DNA replication acyclovir is added to the growing strand rather than GTP. thus halting elongation and stopping replication

amantadine

binds to a transmembrane protein involved in the escape of influenza virus from endosomes

tamiflu &relenza

neuraminidase inhibitors. target influenza by blocking the acivity or neuraminidase thus preventing the virus from being released from the cells

Azidothymidine

reverse transcriptase inhibitor. Block the conversion of RNA genome into DNA

Ritonavir

protease inhibitor. blocks the processing of viral proteins and prevents viral maturation

What are the different ways an anti-retro-viral can block a virus ?

1. block receptors

2. block reverse transcriptase

3. block integration into the cells DNA

4. blocks proteins and release of the virus

What are some mechanisms for drug resistance

efflux pumps, blocked penetration, inactivation of enzymes, and target modification

Inactivation

resistance genes may code for enzymes that chemically modify an antimicrobial, inactivating it or destroying it via hydrolysis

Efflux

microbes develop a resistance that involves inhibiting the accumulation of an antimicrobial drug preventing it from reaching its target.

Target modification

Since antimicrobial drugs are target specific a structural change to that target can prevent the drug from binding thus making it ineffective

Target Overproduction

bacteria will overproduce enzymes that are the targets of antibiotics so that function will continue as antibiotics bind to extra components

Target mimicry

production of proteins that bind and sequester drugs, preventing the drugs from binding to their target

MDR's

Multi-Drug Resistant microbes " superbugs" with one or more resistance mechanisms

Cross resistance

A single resistance mechanism that confers resistance to multiple antimicrobial drugs

MRSA

Methicillin-Resistant Staphylococcus Aureus; oppourtunistic pathogens. A particular concern for skin and other owund infections.

Can be acquired in a hospital or community

Vancomycin- resistance bacteria

VRE, VRSA, VISA. need rapid clinical identification so that proper procedures can be used to limit the spread

MDR-TB

Multi-drug resistant Mycobacterium tuberculosis

XDR-TB

extensively drug resistant TB

Kirby-Bauer Test

Antibacterial activity obserced as a clean zone of inhibition around a drug impregnated disk

Zone of inhibiton

the diameter measured in mm, compared to a standardized chart. the susceptibility or resistance of bacteria

What are some factors that determine the size of the inhibition zone

Drug solubility, rate of drug diffusion, thickness of agar, and drug concentration of impregnated disk