Antimicrobial Drugs

chemotherapy

The treatment of disease using chemical substances called chemotherapeutic agents.

selective toxicity

The ability of a drug to harm the infectious agent while causing minimal harm to the host.

What must chemotherapeutic agents do to be effective in the body?

Penetrate tissues, reach microbes at effective concentrations, and not interfere with host immune defenses.

antibiotics

Chemotherapeutic agents produced by microorganisms that inhibit or kill other microbes in small amounts.

First discovered antibiotic

Penicillins

organisms commonly produce antibiotics

Bacteria - Streptomyces and Bacillus and fungi - Penicillium and Cephalosporium

Why are bacterial infections easier to treat than viral infections?

Bacteria have structures and pathways different from human cells that can be targeted by drugs.

three bacterial features targeted by antibiotics.

Cell wall, bacterial ribosomes, and unique metabolic pathways

viral infections difficult to treat with chemotherapy

Viruses replicate inside host cells using the host's machinery

fungal, protozoan, and helminth infections harder to treat

Their cells are eukaryotic and very similar to human cells, limiting selective toxicity.

spectrum of activity

The range of microorganisms that an antibiotic can kill or inhibit.

narrow-spectrum antibiotic

An antibiotic that is effective against a limited group of bacteria

broad-spectrum antibiotic

An antibiotic that is effective against a wide range of bacteria, including Gram-positive and Gram-negative

When are broad-spectrum antibiotics commonly used

When rapid treatment is needed and the pathogen is unknown

disadvantage of broad spectrum antibiotics

They can kill normal microbiota and cause superinfections.

superinfection

An overgrowth of an opportunistic pathogen that is not affected by the antibiotic.

Why narrow-spectrum antibiotics preferred

Reduce damage to normal microbiota and lower the risk of superinfection.

Classifications of antibacterial drugs

spectrum of activity, bactericidal vs bacteriostatic effect, chemical structure, and mode of action.

bactericidal antibiotics

antibiotics that kill bacteria

bacteriostatic antibiotics

Antibiotics that inhibit bacterial growth, allowing host defenses to eliminate them.

Why classify antibiotics by chemical structure?

Drugs with similar structures often have similar mechanisms of action

major modes of action of antibacterial drugs

Inhibition of cell wall synthesis, protein synthesis, nucleic acid synthesis, plasma membrane damage, and inhibition of essential metabolites.

Why are cell wall-targeting antibiotics selectively toxic to bacteria?

Because peptidoglycan is found only in bacterial cell walls, not in human cells.

transpeptidation

The final step of peptidoglycan synthesis where peptide cross-links are formed.

enzymes catalyze transpeptidation

Transpeptidases, also called penicillin-binding proteins

penicillins kill bacteria

inhibit the transpeptidase enzyme involved in the formation of peptide crosslinks during peptidoglycan synthesis

Why are penicillins only effective against actively growing bacteria?

Because peptidoglycan cross-linking occurs only during cell growth.

structural feature defines all penicillins

β-lactam ring

Penicillinases (B-lactamases)

Enzymes that break the β-lactam ring and inactivate penicillins

Methicillin-resistant Staphylococcus aureus

a type of infectious bacteria that is highly resistant to treatments such as antibiotics, like methicillin. strain of staphylococcus aureus

semisynthetic penicillins

part is natural produced by mold and part is modified, designed to improve spectrum, resist β-lactamases and overcome pencillinases

Natural penicillin

produced from penicillium mold, narrow spectrum and are susceptible to penicillinases

Penicillinases

enzymes produced by bacteria that cleave the beta-lactam ring

Penicillinase-Resistant Penicillins

designed to resist cleavage by penicillinases (beta-lactamases)

methicillin

Type of Penicillinase-Resistant Penicillins

Extended-Spectrum Penicillins

semisynthetic penicillins with broad spectrum activity, effective against many Gram-negative and Gram-positive bacteria. Not resistant to penicillinases

examples of Extended-Spectrum Penicillins

aminopenicillins and carboxypenicillins

purpose of β-lactamase inhibitors

To protect penicillins from degradation by β-lactamases

penicillin/β-lactamase inhibitor combination

strategy to combat resistance due to penicillinases is to use drug combinations

clavulanic acid

commonly used β-lactamase inhibitor

Cephalosporins

structurally related to penicillins, inhibit peptidoglycan synthesis in same way as penicillins, are susceptible to cephalosporinases (beta-lactamases)

First generation cephalosporins

narrow spectrum, active mainly against Gram-positives. ex. Cephalexin

second generation cephalosporins

more extended Gram-negative spectrum. ex. Cefamandole

Third Generation Cephalosporins

Most active against Gram-negatives, including some pseudomonads. ex. Ceftazidime and Cefixime

forth generation cephalosporins

Have the most extended spectrum of activity - good activity against both Gram-positives and Gram-negatives. ex. Cefepime

Carbapenems function

β-lactam antibiotic, inhibit peptidoglycan synthesis in the same way as penicillins and cephalosporins

Carepenems

extremely broad spectrum of activity and last rest antibiotic for gram negative

Bacitracin

polypeptide antibiotic named after its source, effective primarily against Gram-positive bacteria. Topical treatment

How bacitracin inhibit cell wall synthesis

interferes with the synthesis of the peptidoglycan, the formation of the carbohydrate backbone.

how vancomycin inhibit cell wall synthesis

It blocks peptide cross-link formation by a mechanism different from β-lactams.

What bacteria is vancomycin mainly effective against

narrow spectrum, Gram-positive bacteria. also a last resort for treatment of Staphylococcus aureus infections

What are VRE and VRSA?

Vancomycin-resistant enterococci and Staphylococcus aureus.

Teixobactin

newly discovered antibiotic that inhibits peptidoglycan synthesis in Gram-positive bacteria.

technology was used to discover teixobactin

The iChip, which allows growth of unculturable bacteria.

What is unique about mycobacterial cell walls?

They contain mycolic acids

isoniazid INH function

It inhibits synthesis of mycolic acids.

ethambutol (EMB) function

It prevents incorporation of mycolic acids into the cell wall.

Antimycobacterial Drugs

Target mycobacterial cell walls like tuberculosis,

why can antibiotics selectively target bacterial protein synthesis?

Bacteria have 70S ribosomes, while eukaryotic cells have 80S ribosomes

Why can protein synthesis inhibitors cause side effects in humans?

Human mitochondria contain 70S ribosomes, similar to bacterial ribosomes

ribosomal subunit aminoglycosides target

30S

Aminoglycosides spectrum activity

broad spectrum, target gram positive and gram negative

aminoglycosides inhibit protein synthesis

They cause misreading of mRNA by altering the shape of the 30S subunit.

major side effects of aminoglycosides

Neurotoxicity (hearing loss) and nephrotoxicity (kidney damage)

examples of aminoglycosides

Streptomycin, gentamicin, neomycin, tobramycin

Tetracyclines spectrum activity

broad spectrum which causes superinfections

Tetracyclines inhibit protein synthesis

bind to the 30S subunit and prevent binding of minoacyl-tRNA binding to mRNA ribosome

common tetracyclines

Doxycycline, tetracycline, oxytetracycline

What are glycylcyclines related to?

Tetracyclines

glycylcyclines effective against

tetracycline-resistant bacteria, ribosomal protection and other antibiotic resistant bacteria

Glycylcyclines spectrum activity

broad spectrum and have bacteriostatic effect

glycylcycline antibiotic

Tigecycline

Macrolides inhibit protein synthesis

block the mRNA tunnel in 50S

Macrolides spectrum activity

broad spectrum similar to penicillin,

infections macrolides commonly used for

staphylococcal/streptococcal infections, Legionella, Mycoplasma pneumonia

Common macrolides

erythromycin, clarithromycin, azithromycin

Fidaxomicin (Dificid) used for

macrolide used specifically for clostridioides difficile infection

Streptogramins

They contain two drugs that act synergistically that bind to 50S at different sites and interfere with translation. Bactericidal

streptogramin drug

Synercid

resistant bacteria streptogramins used against

VRE and VRSA

oxazolidinones developed for

To treat vancomycin-resistant infections, bacteriostatic

oxazolidinones function

bidn to P-site of 50S subunit and prevent formation of initiation complex during translation

oxazolidinone drug

Linezolid and tedizolid

main mechanism of antibiotics that injure the plasma membrane

They disrupt the membrane's integrity, causing uncontrolled movement of substances, loss of cell contents, and bacterial cell death.

type of antibiotic is Polymyxin B

bactericidal, narrow-spectrum antibiotic

Polymyxin B primarily effective against

Gram-negative bacteria, including Pseudomonas

Polymyxin B damage bacterial cells

It interacts with LPS and phospholipids, damaging the Gram-negative outer membrane.

Where Polymyxin B commonly used

In topical antibiotic ointments, often combined with bacitracin or neomycin

type of antibiotic is Daptomycin

lipopeptide, bactericidal antibiotic

bacteria is Daptomycin primarily effective against

Gram-positive bacteria, including MRSA, VRSA, and VRE

Daptomycin function to kill bacteria

It forms pores in the plasma membrane, causing ion leakage and cell death.

main effect of inhibitors of nucleic acid synthesis

They prevent bacteria from making DNA or RNA, stopping replication and transcription.

Rifamycins

antibiotic that inhibits synthesis of mRNA

example of a rifamycin and a major use

Rifampin; used in multidrug treatment for tuberculosis

side effect of rifampin

Causes orange-red discoloration of urine, sweat, saliva, and tears.

Quinolones and fluoroquinolones.

antibiotics inhibit enzyme needed for DNA replication

Quinolones and fluoroquinolones spectrum

broad spectrum and bactericidal antibiotics

infections are quinolones/fluoroquinolones commonly used to treat

Urinary tract infections and certain types of pneumonia

major drawback of quinolones and fluoroquinolones

Bacterial resistance can develop rapidly with overuse.

quinolone and fluoroquinolones examples

Nalidixic acid, Ciprofloxacin, Gatifloxacin, Moxifloxacin