Chapter 13: Antimicrobials

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bacteriostatic drugs

cause a reversable inhibition of growth, with bacterial growth restarting after elimination of the drug

bactericidal

kill the target bacteria; essential of the successful treatment of infections in immunocompromised patients

diversity of targeted bacteria

the spectrum of activity of an antibacterial drug relates to what?

narrow-spectrum antimicrobial

targets only specific subsets of bacterial pathogens (ex. only gram-positive bacteria or only gram-negative bacteria); if the pathogen has been identified, it is best to use this and minimize collateral damage to the normal microbiota

broad-spectrum antimicrobial

• targets a wide variety of bacterial pathogens (including gram+ and gram- species) and is frequently used as empiric therapy to cover a wide range of potential pathogens while waiting on lab identification of the pathogen

• used for polymicrobic infections

• may be selected to treat an infection when a narrow spectrum drug fails bc of development of drug resistance by the target pathogen

superinfection

• a secondary infection in a patient having a preexisting infection

• develops when the antibacterial intended for the first infection kills the protective microbiota and allows another pathogen resistant to the antibacterial to proliferate and cause a secondary infection

common examples of superinfections

yeast infections (candidiasis) and pseudomembranous colitis caused by Clostridium difficile

dosage

• the amount of medication given during a certain time interval

• determined to ensure optimum therapeutic drug levels without causing significant toxicity

toxicity

side effects

factors to consider when determining dosage

mass and how drugs are metabolized

half life

rate at which 50% of a drug is eliminated from the plasma

dose dependent drugs

more effective when administered in large doses to provide high levels for a short amount of time

time dependent drugs

more effective when lower optimum levels are maintained over a longer period of time

route of administration

the method used to introduce a drug into the body

niclosamide

treats for tapeworms

colistin

decontaminates the bowels

bacitracin, polymyxin, several antifungals

not easily absorbed by the GI tract so they are applied as topical preps

parenteral route

• intravenous or intramuscular injection

• preferred and typically performed in health-care settings

synergistic interaction

when two antibacterial drugs are administered together that is better than the efficacy of either drug alone

trimethoprim and sulfamethoxazole (bactrim)

when used alone, only provides a bacteriostatic effect, but when used together are bactericidal

antagonistic interactions

• when two drugs combine and produce harmful effects

• can cause loss of drug activity, decreased therapeutic levels, or increased toxicity

the issue with TB

it is becoming drug-resistant

problem with antibiotics

they are demanding them for diseased that do not require them and people are becoming more resistant to them

directly observed therapy (DOT)

the supervised administration of medications to patients

selective toxicity

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

antimicrobial drugs

are what they are because the prokaryotic cells provides a greater variety of unique targets for selective toxicity

mode of action

the when in which the drug affects microbes at the cellular level

mode of action: inhibit cell wall biosynthesis

target: penicillin-binding proteins, peptidoglycan subunits, peptidoglycan subunit transport

mode of action: inhibit biosynthesis of proteins

target: 30S ribosomal subunit, 50S ribosomal subunit

mode of action: disrupt membranes

target: lipopolysaccharide (inner and outer membranes)

mode of action: inhibit nucleic acid synthesis

target: RNA, DNA

mode of action: antimetabolites

target: folic acid synthesis enzyme, mycolic acid synthesis enzyme

mode of action: mycobacterial adenosine triphosphate (ATP) inhibitor

target: mycobacterial ATP synthase

target: penicillin-binding proteins

drug class: (beta)-lactams: penicillins, cephalosporins, monobactams, carbapenems

target: peptidoglycan subunits

drug class: glycopeptides

target: peptidoglycan subunit transport

drug class: bacitracin

target: 30S ribosomal subunit

drug class: aminoglycosides, tetracyclines

target: 50S ribosomal subunit

drug class: macrolides, lincosamides, chloramphenicol, oxazolidinones

target: lipopolysaccharide (inner and outer membranes)

drug class: polymyxin B, colistin, daptomycin

target: RNA

drug class: rifamycin

target: DNA

drug class: fluoroquinolones

target: folic acid synthesis enzyme

drug class: sulfonamides, trimethoprim

target: mycolic acid synthesis enzyme

drug class: isonicotinic acid hydrazide

target: mycobacterial ATP synthase

diarylquinoline

osmotic lysis

what becomes more susceptible when antibacterials block steps in the biosynthesis of peptidoglycan

β-lactams

characterized by the presence of a β-lactam ring found within the central structure of the drug molecule

β-lactam antibacterials

block the crosslinking of peptide chains during the the biosynthesis of new peptidoglycan in the bacterial cell walls; able to block because the structure is similar to the structure of the peptidoglycan subunit that is recognized by the crosslinking enzyme

transpeptidase (penicillin-binding protein)

crosslinking enzyme that recognizes the β-lactam structure

semisynthetic β-lactam drugs

have been developed with changes to he R groups to have increased potency, spectrum of activity, longer half lives, etc

penicillin G and penicillin V

natural antibiotics from fungi and are primarily active against gram+ bacterial pathogens, and a few gram- bacterial pathogens like Pasteurella multocida

aminopenicillins

• i.e., ampicillin and amoxicillin

• are made by adding an amino group (-NH₂) to penicillin G

• increased spectrum of activity against more gram- pathogens

hydroxyl group (-OH)

added to amoxicillin to increase acid stability which allows for improved oral consumption

methicillin

• a semisynthetic penicillin that was developed to address the spread of penicillinases

• made from a change in the r-group of penicillin G to the more bulky dimethoxyphenyl group, which provided protection of the β-lactam ring

• first penicillinase-resistant penicillin

Penicillinases

enzymes produced by some bacteria that can break down penicillin, making the antibiotic ineffective

cephalosporins

• contain a β-lactam ring fused to a six-member ring rather than the five-member ring found in penicillins

• block the transpeptidase activity of penicillin-binding proteins

• have an increased resistance to enzymatic inactivation by β-lactamases

cephalosporin C

• originally isolated from the fungus Cephalosporium acremonium

• similar spectrum of activity to penicillin against gram+ and increased activity against gram-

• posesses 2 R groups which allows for greater diversity

r group

a placeholder for any group of atoms attached to a molecule

semisynthetic cephalosporins

• large family; labeled by generation

• one of the 5th gen has been developed to be active against methicillin resistant Staphylococcus aureus (MRSA)

carbapenems and monobactams

have a β-lactam ring and inhibit the transpeptidase activity of penicillin-binding proteins

aztreonam

only monobactam used clinically

imipenem, meropenem, doripenem

• semisynthetic drugs from the carbapenem family

• provide a very broad-spectrum activity against gram+ and gram- bact. pathogens

vancomycin

• member of the glycopeptides

• a natural antibiotic from the actinomycete Amycolatopsis orientalis

• inhibits cell wall biosynthesis andis bactericidal

• does not directly inactivate penicillin-binding proteins, instead creates a strucural blockage on the end of the peptide chain of cell wall precursors that stops the cell wall subunits from being incorporated in transglycosylation

• also blocks transpeptidation

• bactericidal against gram-positive bacterial pathogens, but it is not active against gram-negative

transglycosylation

a process in bacteria where sugar molecules (specifically N-acetylglucosamine and N-acetylmuramic acid) are linked together to form a long chain

bacitracin

• a group of structurally similar peptide antibiotics originally isolated from Bacillus subtilis

• blocks the cell activity of a specific cell membrane molecule that is responsible for the movement of peptidoglycan precursors, preventing their incorporation into the cell wall

• effective against gram+ organisms found on the skin such as Staphylococcus and Streptococcus

• can be administered orally or intramuscularly

• can be nephrotoxic so it is combined with neomycin and polymyxin in topical ointments like Neosporin

70S cytoplasmic ribosomes

structurally different from the ones in animal cells so they are a selective target for antibacterial drugs

aminoglycosides

• large, highly polar antibacterial drugs that bind to the 30S subunit of bacterial ribosomes, impairing the proofreading ability of the ribosomal complex

• causes a mismatch between codons and anicodons

streptomycin, gentamicin, neomycin, and kanamycin

• aminoglycosides

• potent broad spectrum antibacterials

• nephrotoxic, neurotoxic, and ototoxic

tetracyclines

• bind to the 30S subunit

• bacteriostatic

• inhibit protein synthesis by blocking the association of tRNAs with the ribosome during translation

• broad spectrum

streptomyces

produces tetracyclines

doxycycline and tigecycline

semisynthetic tetracyclines

problems with tetracyclines

phototoxicity, discoloration of developing teeth, liver toxicity

polyketides

• naturally produced secondary metabolites

• complex compounds produced in a stepwise fashion through the repeated addition of two-carbon units by a mechanism similar to that used for fatty acid synthesis

macrolides

Broad-spectrum, bacteriostatic drugs that block the elongation of proteins by inhibiting peptide bond formation; bind to the 50S subunit

erythromycin

• first macrolide

• isolated from Streptomyces erythreus

• prevents translocation

azithromycin

• semisynthetic macrolide

• has a broader spectrum of activity, fewer side effects, and significantly longer half life than erythromycin

telithromycin

• semisynthetic macrolide

• first ketolide

• serious hepatotoxicity

lincomycin and semisynthetic clindamycin

• lincosamides

• similar in mode of action to macrolides

• particularly active against streptococcal and staphylococcal infections

chloramphenicol

• bind to the 50S subunit

• produced by Streptomyces venezuelae

• easily synthesized

• used to treat a wide range of infections (meningitis, typhoid fever, conjunctivitis)

• can cause lethal gray baby syndrome, suppression of bone marrow production and anemia

chloramphenicol anemia

can cause the targeting of mitochondrial ribosome within hematopoietic stem cells or idiosyncratic which involves an irreversible lethal loss of blood cell production known as aplastic anemia

oxazolidinones (inc. linezolid)

• broad spectrum synthetic protein synthesis inhibitors

• binds to the 50S subunit of gram+ and gram-

• interfere with formation of the initiation complex for translation and prevent translocation from A side to P site

metronidazole

• semisynthetic member of the nitroimidazole family that is also a antiprotozoan

• interferes with DNA replication in target cells

rifamipin

• an semisynthetic member of the rifamycin family

• functions by blocking RNA polymerase activity in bacteria

• hetpatotoxic

what does RNA polymerase enzymes being different in bacteria do?

it allows for selective toxicity against bacterial cells; i.e. tuberculosis

nalidixic acid

• a byproduct during the synthesis of chloroquine

• selectively inhibits the activity of bacteria DNA gyrase, blocking DNA replication

chloroquine

a antimalarial drug

fluoroquinolones

• i.e., ciprofloxacin, levofloxacin

• chemically modified versions of the og quinolone backbone

• inhibit the activity of DNA gyrase

ciprofloxacin and levofloxacin

• effective against a broad spectrum of gram-pos or gram-neg bacteria and treat a wide range of infections (urinary tract, respiratory, abdominal, skin)

• side effects include phototoxicity, neurotoxicity, cardiotoxicity, glucose metabolism dysfunction, and increased risk for tendon rupture

antimetabolites

competitive inhibitors for bacterial metabolic enzymes

sulfonamides (sulfa drugs)

• oldest synthetic antibacterial agents

• structural analogues of para-aminobenzoic acid (PABA)

• inhibits the enzyme involved in the production of hydrofolic acid and block the bacterial biosynthesis of folic acids and, subsequently, pyrimidines and purines needed for nucleic acid synthesis

• bacteriostatic against gram-pos and neg pathogens

• selectively toxic for bacteria but may cause an allergic reaction

para-aminobenzoic acid (PABA)

an early intermediate in folic acid synthesis

sulfones

• structurally similar to sulfonamides

• used for the treatment of Hansen’s disease (leprosy)

trimethoprim

• synthetic antimicrobial compound that serves as an antimetabolite like a sulfonamide but is a structural analogue of dihydrofolic acid and inhibits a later step in the metabolic pathway

• used with sulfamethoxazole to treat urinary tract infections, ear infections, and bronchitis

trimethoprim and sulfamethoxazole

• used together to treat to treat urinary tract infections, ear infections, and bronchitis

• when used together is bactericidal

• should be used carefully during pregnancy

isoniazid

• antimetabolite with specific toxicity for mycobacteria

• used in combo with rifampin or streptomycin to treat TB

• administered as a prodrug, requiring activation through the action of an intracellular bacterial peroxidase enzyme, forming isoniazid-NAD and isoniazid-NADP, preventing the synthesis of mycolic acid, which is essential for mycobacterial cell walls

• possible side effects are hepatotoxicity, neurotoxicity, and anemia

prodrug

a medication that is not active when you take it. Instead, it becomes active only after your body processes it

bedaquiline

• diarylquinoline

• inhibits mycobacterial growth through interference with the function of ATP synthases, possibly by interfering with the use of the hydrogen ion gradient for ATP synthesis by oxidative phosphorylation

• because of its side effects (hepatotoxicity and potentially lethal heart arrhythmia), it is only used for extreme cases of TB when absolutely needed

disruption of the cell membrane

the most common mode of action for antifungal drugs

antifungal drugs

take advantage of the biochemical pathways that synthesize sterols

sterols

important in maintaining proper membrane fluidity and therefore proper function of the cell membrane

ergosterol

• predominant membrane sterol in fungi cell membranes

• targeted by antifungal drugs