L19 Flashcards
Antimicrobial agents
Agents that kill or inhibit growth of microbes
Physical or chemical - have no or low selectivity
Chemical antimicrobial agents
- chemotherapeutic agents = antimicrobial drugs or antimicrobials, including:
- antibiotics = microbial products or derivatives e.g. penicillin
- synthetic antimicrobials e.g. sulphonamides
The modern era began with the work of German physician Paul Ehrlich. What did he do
- Dyes can bind to microbial cells
- 1910: magic bullet- arsenic based salvarsan to treat SYPHILIS
1927: GERARD DOMAGK discovered what
- Prontosil red, a coal-tar dye for staining
leather, had antibiotic properties - treat streptococcus infections
- active ingred: sulphanilamide
1928: The first antibiotic, penicillin, discovered by Alexander Fleming
- S. aureus with mould that killed staphylococcus
- mould: Penicillium notatum, which produced penicillin G – diffused into agar – lysed bacteria
Florey & Heatley
- improved penicillin
1944: next was streptomycin
TB drug
Broad spectrum
- inhibits/kills a broad range of microbes
- Tetracycline inhibits Gram-ve, Gram+ve, Chlamydia, Rickettsia
Narrow spectrum
- inhibits/kills narrow range of microbes
- specificity due to the differences in their cell envelope structures
Static agents
- growth is inhibited but no killing occurs
- upon removal of the agent the microbe will recover and resume growth
Chloramphenicol static or cidal
bacteriostatic
Cidal agents
- cidal agents result in irreversible microbe death, some cause cell lysis
Penicillins static or cidal
bactericidal
Antimicrobial drugs must be selectively toxic bc?
- kill or inhibit microbial pathogen
- damage host as little as possible
§ toxic dose:
dose at which drug becomes too toxic for the host
therapeutic dose:
dose needed to treat the infection
Therapeutic Index
Therapeutic dose
The ____ the therapeutic index, the better the chemotherapeutic agent
larger
targets of antibiotic action
- Inhibitors of protein synthesis
- Inhibitors of cell wall synthesis
- Metabolic antagonists/antimetabolites
- Inhibitors of DNA/RNA synthesis
- Cell membrane disruption
- Inhibitors of protein synthesis
- Selective toxicity is fairly good, they target bacterial ribosomes, not eukaryotic ribosomes
- aminoglycosides
- tetracyclines
- macrolides
- chloramphenicol
aminoglycosides
- cidal
- bind to 30S subunit of ribosome, cause misreading of genetic code
- streptomycin
- Broad
- mainly aerobic Gm –ve’s
tetracyclines
- static
- bind to 30S subunit of the ribosome
- tetracycline, doxycycline
- Broad - bacteria
macrolides
- static
- bind to 23S rRNA of 50S subunit
- erythromycin
- broad (good for anaerobes)
chloramphenicol
- static
- bind to 23S rRNA of 50S subunit
- chloramphenicol
- broad (most bacteria)
Broad Inhibitors of protein synthesis
Tetracyclines, macrolides, chloramphenicol
- Inhibitors of cell wall synthesis
- Selective toxicity excellent, they target bacterial cell wall which is not present in eukaryotic cells
- penicillins - cidal - inhibit transpeptidations enzymes - penicillin G narrow - ampicillin braod
penicillins
(β-lactams)
- cidal
- inhibit transpeptidation enzymes (=penicillinbinding proteins or PBPs) involved in cross-linking peptidoglycan cell wall
- penicillin G, methicillin –> narrow (Gm+ve only)
- ampicillin, piperacillin–> broad (Gm+ve, & some Gm-ve)
Penicillins contain β-lactam ring, what does it do?
- resembles the terminal Dalanyl-D-alanine of the peptides
- Thus penicillins block cross-link formation
- Growing cell wall becomes less able to resist osmotic pressure - penicillins lyse growing cells
Semisynthetic penicillins
- to overcome limitations with natural
- New side chains added to β-lactam ring
- Advantages: broader spectrum of activity, acid stability so can be taken orally, resistance to some penicillinases
Natural penicillins produced by
Penicillium fungus (penicillin G,
penicillin V, active against Gram
positives, have limitations
- Pen G destroyed by stomach acid, so must be given by injection
- Penicillin-resistance via penicillinases soon developed
penicillin G, penicillin V B/N
narrow (Gm+ve only), G is acid-sensitive, penicillinase-sensitive
[B/N] ampicillin
broad, (Gm+ve and Gm – ve), acid-stable
[B/N]
narrow (Gm-ve including Ps. aeruginosa)
[B/N] methicillin
narrow, anti-Staphylococcus (MRSA)
[B/N] piperacillin
extended spectrum (many Gm+ & Gm-ve, resistant to many but not all penicillinases)
cephalosporins (β-lactams) characteristics
- Cidal
- MoA: contain βlactam ring
- cefalexin, cephalothin,cefoxitin
- broad (Gm+ve, some Gmve), useful if penicillin allergy
vancomycin characeristics
- Cidal
- MoA: inhibits transpeptidation, binds to D-ala-Dala so differs from penicillins (its not accessible)
- vancomycin
- narrow (Gm+ve), drug of last resort in some cases e.g. MRSA, enterococci. *ototoxic, nephrotoxic
- Metabolic antagonists/antimetabolites
- Humans don’t synthesise folic acid
- sulfonamides (e.g. SMX) inhibit folic acid synthesis
- trimethoprim blocks later step in folate cycle
- high synergism: less of each drug needed in combination than when alone
- THF needed to form DNA bases (A, G, T) and methionine in bacteria
high synergism:
less of each drug needed in combination than when alone
- Inhibition of nucleic acid synthesis
- Poor selective toxicity because bacteria and eukaryotes have similar nucleic acid synthesis pathways – but still very useful agents
- quinolones and fluoroquinolones (synthetic drugs)
- rifampin/rifampicin
rifampin/rifampicin
- cidal
- inhibits RNA polymerase: blocks mRNA synthesis
- rifampicin
- narrow, used for TB, leprosy, and some Gm-ves
- Cell membrane disruption
- Poor selective toxicity as bacterial and human membranes are very similar in
structure - polymyxins
polymyxins characteristics
- cidal
- Disrupt plasma membrane, detergent-like activity
- polymyxin B, polymyxin E = colistin
- Narrow, topical use for Gm-ve’s e.g. Ps. aeruginosa Colistin is drug of last resort for multiply-antibiotic-resistant Gm-ve’s
polymyxins tox and fact
- High toxicity, kidney damage, neurotoxicity * Drugs of last resort for some multi-resistant Gram negative bacteria e.g. Ps. aeruginosa, Klebsiella pneumoniae
- Metabolic antagonists/antimetabolites info
- structurally similar to enzyme substrate, so compete with metabolite
- block enzyme activity, thus block a metabolic pathway
- can have good selective toxicity as host lacks pathway, or host enzyme differs from bacterial enzyme
- sulfonamides (sulfa drugs)
- trimethoprim (synthetic drug)
Sulfonamides (sulfa drugs)
- static
- inhibit folic acid synthesis by competing with pABA
- sulfanilamide, sulfamethoxazole
- broad
trimethoprim (synthetic drug)
- static
- inhibits folic acid synthesis by inhibiting enzyme DHF reductase
- trimethoprim (often used in combination with a sulfonamide as synergistic* )
- broad, Tp/Su= Cotrimoxazole combination is widely used
