• inhibition of peptidoglycan biosynthesis in cytoplasm
• analog of PEP

• inhibtion of peptidoglycan biosynthesis in cytoplasm
• analog of D-alanine
• inhibits alanine racemase and D-ala-D-ala synthesis

• inhibition of peptidoglycan intermediates in periplasm
• binds diphosphate on carrier lipid that brings peptidoglycan subunits to periplasm, preventing reactivation

• binds to D-ala-D-ala side chain of membrane bound precursor
• blocks both peptidoglycan chain extension and transpeptidation
• narrow spectrum --> gram+ organisms
• drug of choice against MRSA and C. difficile

• resistance - change to D-ala-D-lactate that vancomycin can't bind to

• D-ala-D-ala analog
• bacteriocidal
• β-lactam - interferes with transpeptidation
• newer derivatives have different R groups (benzyl penicillin, ampicillin, methicillin, piperacillin)

• resistance - β-lactamase
  • gram+ - inducible, high affinity, large amounts, extracellular
  • gram- - constitutive, lower affinity, smaller amounts, cell bound (periplasm)
• mutations in penicillin-binding proteins
  • enzymes of peptidoglycan cross linking used by cell during cell wall growth

• β-lactams - interfere with transpeptidation
• new generations carry modifications to make them more resistant to β-lactamase or more effective against certain organisms

• resistance - β-lactamase
  • gram+ - inducible, high affinity, large amounts, extracellular
  • gram- - constitutive, lower affinity, smaller amounts, cell bound (periplasm)
• mutations in penicillin-binding proteins
  • enzymes of peptidoglycan cross linking used by cell during cell wall growth

• cationic detergent-like effect on cell surfaces
• low discrimination limits most use to topical applications

• inhibit 30S ribosomal subunit
• extremely bacteriocidal once in the cell
• synergistic with β-lactams
• low therapeutic index and allelic sensitivity
• bacteriocidal
• broad spectrum, bacteriocidal --> slows development of resistance, fewer disturbances of natural flora
• streptomycin, neomycin, kanamycin, gentamycin, tobramycin, amikacin

• resistance
  • inactivation of active transport (permeability)
  • acetylation, adenylation, or phosphorylation of critical groups on aminoglycoside molecule
  • ribosomal protein modifications

• inhibit 30s ribosomal subunit
• block attachment of amino acid-tRNA to mRNA-ribosome complex
• bacteriostatic
• broad spectrum - used to treat intracellular infections (Rickettsia, Mycoplasma, Chlamydia)

• resistance usually due to reduced transport or plasmid encoded effexor pump

• inhibitor of 50S ribosomal subunit
• inhibits peptidyl transferase
• bacteriostatic --> useful in meningitis because it accumulates in CSF, but is toxic

• resistance - plasmid borne genes encoding chloramphenicol acetyl transferase

Macrolides

(Erythromycin, Azithromycin)

• inhibit 50S ribosomal subunit
• block ribosomal translocation
• newer macrolides extend the spectrum
• bacteriostatic (bacteriocidal at higher doses)
• erythromycin drug of choice for Legionella and intestinal Campylobacter

• resistance - plasmid gene which methylates a site in 23S RNA
  • erythromycin stalls ribosomes --> straightens out hairpin --> another ribosome can access the ribosomal methylase start site and synthesize it
• other resistance due to chromosomal mutations in ribosomal proteins or ribosomal RNA

• inhibitors of 50S ribosomal subunit
• similar action and resitance as macrolides
• Clindamycin used to treat serious gram- infections --> pseudomembranous enterocolitis associated with overgrowth of C. difficile

• inhibit bacterial gyrase (Topo-II) and Topo-IV
• man-made --> low resistance
• highly bacteriocidal, broad spectrum, low MIC
• concentrated in urine during excretion

• inhibits RNA polymerase
• important for TB treatment in combo with additional antibiotics

• resistance is a major problem --> chromosomal mutation in β subunit of RNA polymerase

• folate synthesis inhibitor
• analog of PABA that compete for dihydropterate synthetase
• bacteriostatic
• used in combination with trimethoprim

• wide resistance and hypersensitivity

• inhibits folate synthesis
• analog of pteridine portion of folic acid
• inhibits dihydrofolate reductase (inactive against mammalian form)
• bacteriostatic alone, but combined with sulfonamide, synergistic bacteriocidal effects can be achieved

• PABA antagonists used primarily in therapy of Mycobacterium infections

Oxazolidinones

"Zyvox"

• inhits translational initiation

Streptogramins

"Synercid"

• 70% Dalfopristen
  • binds to 50S ribosome and inhibits elongation --> conformational change and ↑ affinity for quinopristen --> premature termination and prevents further initiation
• 30% Quinopristen
  • competes with macrolides for 50S binding
• bacteriocidal with both, bacteriostatic if resistance to one of the components

Daptomycin

"Cubicin"

• in combo with Ca²⁺, interferes with membranes
• useful for gram+ resistant to other antibiotics (MRSA)

• not yet approved
• isolated from natural products from Streptococcus
• discovered to activate a bacterial protease (ClpP) to more efficiently degrade proteins and to degrade proteins not usually degraded by the protease