Chapter 14 (Anti Microbial Drugs) UTA BIOL 2460

chemotherapy

drugs that target living cells / tissue

Antimicrobial drugs

Target microbes

derived from plants

Paul Ehrlich

scanned through 600 arsenic compounds to find a cure for syphilis w/o killing host

(Treponema pallidum)

Josef Klarer, Fritz Mietzch, & Gerhard Domagk

synthetic dye / prontosil----> to treat strep infection

Alexander Fleming

discovered penicillin

Penicillin

First natural antibiotic

Dorothy Hodgkin

used X- rays to analyze the structure of penicillin

Selman Waksman

Studied soil microbes / discovered several antimicrobials

Actinomycetes are the source of >50% of natural antibiotics

semisynthetic antimicrobials

chemically altered antibiotics that are more effective, longer lasting, or easier to administer than naturally occurring antibiotics

-Cidal

Kills

-Static

inhibits

Narrow Spectrum

targets specific group of microbes

Broad Spectrum

Targets wide variety

May cause superinfection

dosage

how much given within a certain timeframe

based on weight for children

Standard for 12+

Route of administration

Oral / topical = cream or ointment / intravenous

synergistic effect

1 + 1 = 2

the two drugs create a greater affect

Ex: trimethoprim + Bactrim

antagonistic

work in opposition of each other

Ex: Rifampin + Birth control

selective toxicity

Kill pathogen and save the host

β-lactams

presence of lactam ring

1. penicillin

2. Cephalosporins

3. carbapenems

4. monobactams

Penicillin

derived from fungi

Mostly G+ / some G-

Cephalosporins

similar to penicillin

resistance to β-lactamases

Carbapenems

broad spectrum against G+/G-

Monobactams

narrow spectrum

G- only

Vancomycin

MOA: binds to end of peptide chain to block subunits from adding to peptidoglycan backbone

G+ only

*Bacitracin

derived from B. subtilis

blocks transport of peptidoglycan precursors

*(1 of 3) Triple antibiotic ointment

Aminoglycosides

Bind to 30S subunit of ribosome and impair "proofreading" ability

Ex: Streptomycin / gentamicin / *neomycin (2 of 3 ) triple antibiotic ointment

Tetracyclines

Bind to 30S

blocks association of tRNA with ribosome

Prominent protein synthesis drugs:

Bind to 50S subunit & inhibit peptide bond formation in specific combos of amino acids

Macrolides

broad spectrum

-static

Ex: Erythromycin / azithromycin

Lincosamides

narrow spectrum

-static

particularly active against streptococcal and staphylococcal infections

Chloramphenicol

broad spectrum

-static

rarely used now because of serious side effects

Prominent protein synthesis drugs

Macrolides

lincosamides

chloramphenicol

Oxazolidinones

bind to the 50S ribosomal subunit and interferes with association of 30S and other factors

Broad spectrum

-static

(Ex. Linezolid)

*Polymyxins

lipophilic & interact w/ LPS to disrupt outer & inner membrane of Gram (-)

mechanism not a selective toxicity

*(3 of 3) Triple antibiotic ointment

What are the three antimicrobial drugs in Neosporin?

1. Bacitracin

2. Neomycin

3. Polymyxins

Daptomycin

cyclic lipopeptide that inserts and disrupts Gram (+) membrane

*Metronidazole

interferes w/ DNA replication

not very selective in toxicity

(targets anaerobic bacteria AND protozoa)

Rifampin

blocks RNA polymerase activity

can treat semi-dormant M. tuberculosis

can be antagonistic & hepatotoxic

Fluoroquinolones

inhibit DNA gyrase enzyme

selective toxicity but many side effects

Broad spectrum

-cidal

Antimetabolites

competitive inhibitors of enzymes to stop certain pathways

Sulfonamides

halts folic acid synthesis and production of pyrimidines & purines

Often used in combo with Trimethoprim

Broad spectrum

-static alone

Trimethoprim

inhibits later stage of folic acid synthesis

Sulfamethoxazale & Trimethoprim are commonly used in combination to boost effect (-cidal)

Isoniazid

specific toxicity for mycobacteria to block synthesis of mycolic acid

Diarylquinolines

inhibits mycobacterial growth

exact mechanisms is unknown but evidence shows interference with ATP synthase and reducing available ATP

Antifungal drugs MOA

disruption of sterol synthesis and membrane integrity

Prominate Antifungal Drugs

Imidazoles

Triazoles

Allylamines

Polyenes

Imidazoles

Disrupt ergosterol biosynthesis

Commonly used in medical and agriculture

Treat infections caused by dermatophytes: ringworm, tinea pedis (athlete's foot), tinea cruris (jock itch)

Triazoles

Inhibit ergosterol biosynthesis

Administered orally or intravenously

Systemic yeast infections: oral thrush, cryptococcal meningitis

Allylamines

Inhibit earlier step in ergosterol biosynthesis

Treat dermatophytic skin infections: athlete's foot, ringworm, jock itch

Terbinafine (Lamisil)

Polyenes

Bind to ergosterol and create pores in the membrane

Flucytosine

interferes with DNA replication and protein synthesis

Echinocandins

Inhibit β(1-3) glucan synthesis

penicillin for fungi

Polyoxins & nikkomycins

Inhibit chitin synthesis

Griseofulvin

Interferes with microtubules involved in spindle formation during mitosis

Atovaquone

antimetabolite for fungal and protozoal mitochondrial cytochrome function

Antiprotozoan Drugs MOA's

1.Inhibition of various metabolites

2.Inhibition of DNA synthesis

Antiprotozoan Drugs

Atovaquone

Proguanil

Metronidazole

Pentamidine

Artemisinin

Quinolines

Atovaquone

inhibits electron transport

Ex: Malaria, babesiosis, toxoplasmosis

Proguanil

inhibits folic acid synthesis

Metronidazole

inhibits DNA synthesis

Ex: Dysentery, Giardia, trichomoniasis

Pentamidine

Cleaves DNA within kinetoplasts; binds tRNA

Ex: African sleeping sickness, leishmaniasis

Artemisinin

Unclear, but likely damages target cells by ROS; antimalarial

Quinolines

Interferes with heme detoxification

Ex: Malaria, dysentery

Antihelminthic drugs

Achieving selective toxicity is challenging

Mebendazole

Inhibition of microtubule formation

Broad range

Ivermectin

blocks neuronal transmission in invertebrates causing starvation, paralysis, and death

Ex: Round worms and parasitic insects

Niclosamide

Inhibit ATP formation under anaerobic conditions

Ex: Intestinal tape worms

Praziquantel

Induce influx of Ca into the worm; paralysis

Ex: Tapeworms, liver flukes, schistosomiasis (blood flukes)

AntiVrial Drugs

Inhibiting nucleic acid synthesis

Acyclovir

Specificity: viral enzyme activation and affinity for viral DNA polymerase

Amantadine & Rimantadine

Treatment of influenza A

Binds to transmembrane protein

Blocking escape from endosome prevents RNA release into host cells

Oseltamivir

Inhibition of neuraminidase that aids in release of viral particles from host cell

Reverse transcriptase inhibitors

block RNA -> DNA

Protease inhibitors

Block processing of viral proteins

Integrase inhibitors

Prevents integration of viral DNA into host chromosome

Fusion inhibitors

Prevent binding of virus to host cell and merging of envelope and membrane

Antibiotic Resistance

Arises from increased selective pressure

Selective pressure increased through

1. Misuse & inappropriate use of antimicrobials

2. Subtherapeutic dosage

3. Patient noncompliance

Resistance genes are obtained how?

Horizontal and Vertical transfer

Mechanisms for Resistance

1. Enzymatic modification or inactivation of the drug

2. Modification of the antimicrobial target

3. Overproduction of antimicrobial target

4. Enzymatic bypass of antimicrobial target

5. Mimicry of antimicrobial target

6. Prevention of drug penetration or accumulation

Efflux Pump

fluoroquinolones

aminoglycosides

tetracyclines

B-lactams

macrolides

blocked penetration

B-lactams

Tetracyclines

Fluoroquinolones

inactivation of enzymes

B-lactams

Ainoglycosides

Macrolides

Rifamycins

target modification

Fluoroquinolones

Rifamycins

Vancomycin

B-lactams

Macrolides

Aminoglycosides

Drug Modification

β-lactamases hydrolyze lactam bond

Target Modification

1. LPS structure alteration to affect polymyxins

2. RNA polymerase alteration to affect Rifampin

Target Overproduction

1. Vancomycin resistance in S. aureus by decreased cross-linkage of peptide chains in cell wall (increase in targets)

Target Mimicry

1. M. tuberculosis produces pentapeptides to mimic DNA and binds to fluoroquinolones

Prevent Accumulation

1. Pathogens produce efflux pump to transport drug out of cell and prevent accumulation

Multidrug-resistant microbes (MDRs)

1. Superbugs

2. 2 million infections per year; 23,000 deaths

Cross-resistance

one mechanism confers resistance to multiple drugs

ESKAPE

Enterococcus

Staphylococcus

Klebsiella

Acinetobacter

Pseudomonas

Enterobacter

Special Resistance in Microbes

1. Vancomycin only effective against G+

2. Last line of defense (including MRSA)

Vancomycin-resistant enterococci (VRE)

Target modification of peptide component in cell wall; prevent binding

Vancomycin-resistant S. aureus (VRSA)

Horizontal gene transfer from patients infected with VRE and MRSA

Vancomycin-intermediate S. aureus (VISA)

Increase in targets; binding to outer cell wall

Methicillin-resistant S. aureus (MRSA)

Acquisition of new low-affinity PBP; resistance to all β-lactams

Extended-spectrum β-lactamases (ESBLs)

1. Resistance to penicillins, cephalosporins, monobactams, β-lactamase-inhibitors, but NOT carbapenems

2. ESBLS found on plasmids that have other drug resistances

Carbapenem-resistant Enterobacteriaceae (CRE)

1. Produce carbapenemases (β-lactamases that inactivate all β-lactams)

2. Efflux pumps and uptake prevention

3. Some have developed pan-resistance (resistance to all antibacterials)

Multidrug-Resistant Mycobacterium tuberculosis (MDR-TB)

Resistant to both rifampin and isoniazid