Antibacterial Agents

antibiotics: few targets but plenty of resistance

- bacteria doubling time = 30 minutes (single cell organisms, asexual cell division)

- single cell organisms means that they do not have a lot of protections (only from membrane - peptidoglycan layer, periplasmic space is much different than ours)

- gram positive = can retail gram stain (membrane is more accessible, similar to human cell)

- gram negative = tough penetrating outer membrane (do not retain dye, harder to treat) - polar, highly charged external membrane

- chemically modified natural structures (overcome resistance, expands targets)

- we want selective agents (not against our cells)

- targets = cell wall, plasma membrane, protein synthesis, DNA/RNA synthesis, metabolism

- cell wall is the biggest target (ex. penicillin)

- protein synthesis is also a large target - ribosome is very different than ours and the drugs are very selective

- changes to the membrane or efflux pumps cause resistance

importance of the bacterial cell wall on antibiotics

gram-positive

- most closely related to us - classic lipid bilayer but with harder external layer called peptidoglycans (can block some uptake of compounds)

- relatively easy to permeate

- increased hydrophobicity, increased permeability (similar to humans)

- efflux pump activity

gram-negative

- thinner peptidoglycan layer, lipopolysaccharides highly negative charge (tough exterior, hydrophobic molecules bounce off this layer - can live in tough evolutionary environments and harder to kill)

- polar compounds on drug molecule (could not get in gram-positive)

- highly impermeable

- ample efflux pumps

- porin transport

- no clear SAR

mycobacteria

- mycolic acid

- highly impermeable (just as bad as gram-negatives)

- wax like coating

- more hydrophobic?

- classified as gram-positive bacteria

agents targeting the cell wall

- b-lactam family (ex. penicillin derivatives) - largest, oldest, most reliant on these derivatives

- glycopeptides (ex. vancomycin)

- lipopeptides (ex. daptomycin)

- fosfomycin

penicillin - a b-lactam

- isolated from the Penicillium fungi

- Fleming reports seeing antibiotic effect from a mold growing on a Petri plate covered with Staphylococcus (Sept. 28, 1928)

- March, 1942 – Merck treated the first patient

- cantaloupe from Peoria, IL best source in 1943

- US produced 2.3 million doses in time for Normandy invasion

- structure determined by Dorothy Crawfoot Hodgkin in 1945

- subject to rapid clearance

SAR

- 4 membered amid is beta-lactam and is most important

- beta = 4 carbon ring (molecule is really strained)

- side chain gets changed

- multiple families within the b-lactams but what we call them changes based on ring to the right

- thiazolidine ring = 5 membered ring in penicillin - sulfur and nitrogen

What tells you that it is a penicillin?

b-lactam and thiazolidine

medicinal chemistry of penicillin

- used to treat infections caused by Gram-positive bacteria (S. aureus, S. pneumoniae, S. pyogenes, E. faecalis)

- mechanism of action:

inhibit formation of peptidoglycan crosslinks in bacterial cell wall

medicinal chemistry of penicillin - SAR

- acyl chain: only location where variation can occur (R=benzyl: Penicillin G)

- strained beta-lactam - strain, resonance of amid is broken (far more reactive, can be attacked by many things)

- free COOH ionized – allows administration as Na+ or K+ salt

- acylamino chain essential

- sulfur is usual but not essential

medicinal chemistry of penicillin - acid sensitivity

- ring strain

- highly reactive beta-lactam carbonyl group

- influence of acyl side chain – incorporate electron-withdrawing groups to reduce sensitivity

medicinal chemistry of penicillin - biosynthesis

- biosynthesis: derives from cysteine and valine

- acyl side chain varies depending on components of fermentation medium (most analoged)

- today: fermented from two strains of penicillium

- dipeptide amino acid mimics D amino acid configuration (most are L configuration) - gives the compound low toxicity because we do not have a lot of things that recognize D amino acids (safe)

penicillin blocks the transpeptidase necessary for crosslinking

- process is specific to the bacterial (not occurring in patients)

- bacteria has D-alanine branching off of peptidoglycan

- want to cross-link them to make them strong via enzyme transpeptidase (penicillin binding proteins - PBPs is the molecular target)

- enzyme looks for 2 D amino acids - penicillin is a D amino acid

- enzyme binds via covalent bond temporarily

- glycine that branches forms bond with D-alanine and turns over the enzyme - stronger membrane (internal pressure swells bacteria if not and it can explode)

transpeptidase cross-linking

- penicillin gets into site and mimics D-ala D-ala unit

- ring open penicillin cannot do the next step

- eventually falls off (quasi-irreversible inhibitors)

there are many PBPs

- tend to have highly conserved active sites (nucleophilic serine)

- chemists can inhibit all of them

- PBPs vary from one bacteria to another

beta-lactamase enzyme confer resistance

- mutated from transpeptidases - do not have transpeptidase activity, no cross-linking

- very efficient: hydrolyze 1000 molecules per second

- contain an active site serine that forms an ester link that is then cleaved to release product

- turnover number is very high, enzyme protects the bug

- antibacterial activity when b-lactam ring is open is gone

- gram-negative (more deadly because more concentrated) and gram-positive

improving penicillins

- reduce acid-catalyzed degradation in stomach

- incorporate electron withdrawing groups to reduce nucleophilicity of side chain carbonyl oxygen, reducing its participation in the ring opening reaction

- acts as a buffer and prevents from acid catalyzation and opening (decreases electron density)

- medications that are oral

– a-aminobenzylpenicillin (ampicillin)

– amoxacillin (very common use)

- Pen-G (iv only)

- do not memorize which is which, just recognize that they are penicillins

gram-positive and gram-negative effects - penicillins

- gram-positive bacteria generally sensitive

- gram-positive just secrete b-lactamases so they are not as concentrated

- gram-negative bacteria: some resistant, some sensitive (hard to get a drug in there)

– depends on structure of porin and structure of penicillin

gram-positive and gram-negative effects - b-lactamase

- some gram-positive bacteria release b-lactamases into surrounding environment

- most gram-negative bacteria produce b-lactamases, usually trapped in periplasmic space

- different b-lactamases vary in substrate specificity

second generation of analogs of penicillin overcome resistance

- analogs present a steric shield to block access to beta-lactamases on amid (large bulky groups slow down beta-lactamases)

- narrow spectrum (gram positive)

- IV delivery

- today: MRSA (methicillin-resistant S. aureus)

carboxypenicillins - broad spectrum

carbenicillin: first example

– COOH gives broad spectrum activity

– increased negative charge (2 charge)

– gram negative active (ilucing P. aeruginosa) but little gram positive

uriedopenicillins - broad spectrum

- derivatives of ampicillin

- more polar side chain enhances gram-negative penetration

- very susceptible to b-lactamases (especially in gram-positive pathogens)

- given iv or im

- good pseudomonial activity

cephalosporins

- still b-lactams but 6 membered dihydrothiazine ring instead of penicillin 5 membered ring

- discovered in mid 1940s, structure established 1961

- isolated from the fungus Acremonium

- has 6-membered dihydrothiazine ring (new scaffold)

- most active against gram(+) but newer versions increased coverage

- developed to have activity against both gram-positive and gram-negative bacteria (H. influenzae, N. gonorrhea, E. coli)

- also has activity in presence of beta-lactamase enzymes, more acid stable

- variations tolerated at 7-acylamino side chain, 3-acetoxylmethyl side chain (unstable) and extra substitution at C7

- 3 acetoxylmethyl side chain unstable because of double bond - swapped out in some medications

first generation cephalosporins (same strategy as penicillins)

- cefalexin (Keflex) both Gram (+) and some Gram (-) but not MRSA

- cefadroxil both Gram (+) and better Gram (-)

- cefazolin good for UTIs, effective for MSSA but not MRSA

- got rid of acetoxy group to simple methyl or ring to increase stability and increase coverage

- change side chain to the left

- MRSA picked up its own PBP

second generation cephalosporins

- cefuroxime has increased resistance to beta-lactamases, retains activity against Streptococci

- cefoxitin and cefotetan have expanded spectrum and are unique in having activity against anaerobic bacteria - given IV/IM

- cefotetan has an N-methylthiotetrazole ring which is a breakdown product and can cause hypoprothrombinemia

third generation cephalosporins

- inclusion of charge on the right and aminothiazole rings (very basic, positively charged, large amounts of charge, increased permeation into gram-negatives)

- replacing furan ring of cefuroxime with aminothiazole ring enhances penetration through membrane of gram-negative bacteria

- variants at position 3 alter PK

- beta-lactamase work in periplasmic space - targets are also located in periplasmic space so for gram-negative, only want to get into outer ring not inner portion

4th generation cephalosporins

- cefepime is the only one!

- offered extended spectrum and higher potency than third generation compounds

- little structural difference with the third generation

even newer (5th generation) cephalosporins

ceftobiprole (2024 US approval)

– activity against Gram-positive and –negative organisms

– binds and inhibits PBP2a from MRSA

ceftaroline (2010)

– similar spectrum as ceftobiprole

– also inhibits PBP2a

a siderophore antibiotic

cefiderocol (2019)

– activity against gram-negative organisms including P. aeruginosa

– exploits the “war for iron” in the body during infection (bacteria need iron to make new bacteria)

– acts as a siderophore and can chelate iron

- right part acts as iron and the bacteria pulls it in and kills the bacteria

- last resort for cUTI

– iv injection only

carbapenem

- last major group of b-lactams

- 5 membered ring but instead of sulfur, there is a carbon

- thienamycin isolated from Streptomyces in 1976

- broad range of activity against gram-positive and –negative

- low toxicity, high resistance to beta-lactamases

- poor metabolic and chemical stability

- imipenem, meropenem and ertapenem are clinically useful analogs - changed how reactive the nitrogen is on the right (increase stability by buffering)

- harder to produce

- have to keep in solution because less stable as a solid

3 main classes of b-lactams

- penicillin

- cephalosporin

- carbapenem

combination with b-lactamase inhibitors

- blocking b-lactamase can protect the drug from enzymatic degradation

- not useful for MRSA since that resistance is due to the insensitive PBP

- undergo suicide reaction with b-lactamase and slow release of covalent complex (bind and never come off)

- compounds do not inhibit the PBPs

clavulanic acid

- inhibits beta-lactamase enzyme

- has beta-lactam ring but no side chain on the left = not a dipeptide, not fooling PBPs into thinking its D-ala, D-ala

- administered with amoxicllin (Augmentin is amoxicillin + CA)

- mechanism-based irreversible inhibitor

clavulanic acid - essential

- b-lactam ring

- enol ether

- Z configuration for double bond

- no substitution at C6

- R at positions 2 and 5

- carboxylic acid group

b-lactamases and their inhibitors

b-lactamases classified by Ambler (A-D)

- A/C/D similar to serine proteases

- class A inhibitors: no activity on their own

b-lactamase class A/C/D (partial)

- spectrum of coverage is the same just protecting from b-lactamase

b-lactamase class B

- (NDM-1) are metalloproteases (no covalent adduct) - no inhibitors

- use zinc

- nothing works on these clinically

glycopeptides/lipoglycopeptides/lipopeptides

huge molecules

- isolation reveals several species from a single source

- most are cyclic, large

- product of the Non-Ribosomal Peptide Synthesis (NRPS) pathway

- frequently contain D-amino acids and/or unnatural amino acids

- many contain non-amino acid moieties

- work almost exclusively on gram-positives

- important against MRSA

vancomycin

- narrow-spectrum agent from Amycolatopsis orientalis

- introduced in 1956 for treatment of penicillin-resistant S. aureus

- main stand-by drug for MRSA

- size makes it unable to cross outer cell membrane of Gram-negative bacteria or inner cell membrane of Gram-positive bacteria

- since cell wall construction takes place outside cell membrane, effective against Gram-+ bacteria

vancomycin structure

- derived from a heptapeptide with 5 aromatic residues

- undergo oxidative coupling to produce 3 cyclic moieties

- chlorination, hydroxylation and addition of 2 sugar units

- cyclizations form rigid unit

- substituents on A,B,C,E important for rigidity (rigid because of cyclic structure)

- hydrogen bonding

- inserts itself into the unit and makes it so the PBPs cannot do anything (hides the substrates) - stops cell wall

vancomycin dimers

- dimers are an important component in the cell wall

- binds to itself in a dimer and binds to d-ala d-ala units

- shuts down

- sugar and chlorine groups also important in dimerization

vancomycin resistance

- vancomycin-resistant S. aureus (VRSA, not common) identified in 1996, and vancomycin-resistant Enterococcus (VRE, more prevalent and a problem) in 1989

- modification of cell wall precursors where terminal D-alanine group replaced by D-lactic acid

- removes an NH group in H-bond, destabilizes the complex and H-bond cannot stick to the D-ala

telavancin

lipoglycopeptide

- synthetic derivative of vancomycin

- approved 2009 for cSSSI

- inhibits bacterial cell wall synthesis

- disruption of bacterial membrane - makes it more leaky

- large lipid tails that associate into gram-positive walls (more gram-positive agents)

long-acting lipoglycopeptides

- very long half-lives (14-15 d), bind strongly to membrane via lipid tail

- uses in skin infections (single dose)

- because they are associated with the membranes, they are not excreted from the body

daptomycin

- lipopeptide antibiotic

- active against gram-positive bacteria

daptomycin MOA

- binds to and causes depolarization of the bacterial cell membrane

- efflux of K+ and other ions, inhibiting macromolecular synthesis

- leaves “ghost cell”

how to tell these apart

- all have peptide

- sugars = glyco

- long fatty tail = lipo

- if it has both = lipoglycopeptide

- name tells you a lot about the structure but probably not on the exam

fosfomycin

- epoxide 3 membered strained ring and super negatively charged

- inhibits the bacterial enzyme MurA needed for synthesis of peptidoglycan

- mimics phosphoenolpyruvate

- irreversible Inhibitor, needs active transport

- used for UTI, concentrates in the urine

antibiotics that inhibit peptide synthesis

- tetracyclines (doxycycline) - most important/most used

- macrolides (erythromycin)

- aminoglycosides (gentomycin)

- oxazolidinones (linezolid) - the only synthetic ones

- lincomycins (clindamycin)

- most are natural product derived

- the way bacteria makes peptides and proteins are the same exact way we make peptides and proteins

- very safe compounds, most drugs have no action against human protein synthesis

- some shut off mitochondrial synthesis

ribosomal assembly

- bacteria have 2 subunits of ribosomes

- 30S is mRNA binding site

- more than one binding site in ribosome for drugs (know where they work) - different in how they inhibit protein synthesis

- not a lot of cross resistance

tetracycline (1953)

- produced by Streptomyces

- tetracycline means 4 rings

- oxygens on the bottom are 1,3 or 1,2 from each other - get rid of oxygens and they tend not to work

- protein synthesis inhibitor – binds to 30S subunit of bacterial ribosome - bacteria cannot replicate

- used to treat infections caused by Gram-positive and –negative bacteria

- also used for acne

- clinically used embers of the family: tetracycline, doxycycline, minocycline, tigecycline, eravacycline and omadacyline

tetracyclines - clinically

- amphoteric (hydrophilic and hydrophobic surface) - hydrophilic surface is extensive array of oxygen atoms and hydrophobic is ring system

- oxygens can bind metal ions - form chelate as part of MOA with phosphates neutralized by magnesium

- impaired absorption in presence of milk, Ca2+, Mg2+, Al3+ - containing antacids (antagonize action via metal chelation)

- side effects: GI problems

- incorporation into bones and teeth (because of Ca2+ binding) - discoloration of the teeth

tetracyclines - mechanism of action

- bind to 30S ribosome

- prevent binding of aa-tRNA to the mRNA-ribosome complex (block adding the next amino acid to the peptide chain)

- binding requires Mg2+ ions (ribosome is Mg2+ rich because of phosphates)

Where/how does tet bind?

- oxygen atoms coordinate Mg2+

- Mg2+ embedded in phosphates on ribosome and coordinate the drugs

- protonated nitrogen also binds negative phosphate

doxycycline and minocycline (second-generation)

modification of c 6-position

- hydroxyl in tetracycline gave some instability - these 2 derivatives get rid of that

- absence of the 6-OH group increases stability in acids and bases, yields long biological half-life

- absorbed well from GI tract

- doxy = methyl

- mino = minus (nothing)

- minocycline most potent tetracycline (1971)

- these show least Ca2+ binding - advantage

tetracycline - resistance

efflux: tet-A, -E, -G, -H, -K, -L (not important which one each is)

- reduce intracellular concentration of the drug to below critical threshold amount that allow bacteria to survive

- large, massive upregulation

- efflux pumps = pumps the drug out

ribosomal protection: tet-M, -O, -S

- bacteria modify the ribosome to disrupt binding (ex. methylation)

- bacterial protein synthesis apparatus rendered resistant by an inducible cytoplasmic protein

enzymatic oxidation

- bug destroys the drug

- oxidases

- less important than the previous 2 methods

tigecycline (third generation)

- got rid of c 6-hydroxyl

- dimethylglycylamino substitution (group called glycylcycline)

- designed to be active against resistant strains (both Gram-+ and Gram-neg)

- charge helps with gram-neg permeability

- retains broad spectrum

- approved 2005

- 2010 Black Box warning-increase risk of death (cause unknown)

recently approved third generation tetracyclines

- modifications of tigecycline

- more positive charge

- omadacycline, eravacycline

macrolides

- metabolites isolated from soil microorganism, Streptomyces

- early work: isolation, later work: semi-synthetic derivatives to improve PK

- macrolide = big ester (ester linkage in large ring)

- large lactone ring, ketone group, glycosidically linked amino sugar

- lactone ring has 12, 14 or 16 atoms and is often unsaturated (large rings)

- floppy, amphipathic characteristic (all methyls on one side and all oxygens on other side - one binds to target and others face outside)

- dimethylamino group on sugar makes the macrolides bases that form salts (needed, does not work when it is taken away because weakens binding to ribosome)

erythromycin

natural compound from bacteria

- 14-member macrocyclic lactone ring with a sugar and an aminosugar attached

- sugar residues critical for binding and activity

- erythromycin binds the 50S ribosome subunit, inhibits translocation

- unstable to stomach acids – because of ketone and alcohol groups (GI problems, poor pk, massive doses) - internal ring forming reaction (ketal formation and completely inactive but impacts GI motility)

- next generation protected the alcohol

- nitrogen is important, hydroxyl groups form strong contacts

- largely used for gram positive (no permeation, not good for gram negatives)

erythromycin/ribosome complex

- all oxygens point to one face and all methyls face back

- hydroxyls face cytosol, methyls into ribosome - stabilize

clarithromycin

- methylation of alcohol was first trick to block acetal formation

- commonly used (ex. strep throat)

- instead of OH becomes OCH3

azithromycin

- one of the best-selling drugs

- 15-membered ring, N-methyl group incorporated (larger ring)

- carbonyl from erythromycin was not essential - removed carbonyl and inserts a nitrogen

- blocks reaction that destroys drug (smaller dose, better pk)

- more active against Gram-negative infections (incorporation of basic nitrogen, can become protonated and will help with permeation)

- PK: slow release from tissues

macrolide - resistance

MLSB – resistance to macrolides, lincosamides and streptogramin B (acronym) - modifying the target

– methylation of single adenine in 50S subunit - confers large resistance

- destabilizes binding to ribosome

– can be inducible or constitutive

– erm gene (erythromycin ribosomal methylase)

M – resistance to macrolides

– efflux pump

- mef gene (macrolide efflux pump)

- lowers concentration

aminoglycosides

- natural products containing amino sugars (nitrogens on sugars)

- activity against Gram-negative pathogens - a lot of their use

- blocks peptide elongation at the 30S subunit of the ribosome (similar to macrolides)

- not absorbed well, given IV, IM or topical or drops (hard to give oral - too polar) - makes more highly concentrated solutions

- major side effect is hearing loss (ototoxicity - impact of mitochondrial protein synthesis) and renal toxicity

aminoglycosides - drugs

- complex shape

- 5 or 6 membered rings with oxygens = glycosides (sugars)

- glycosidic linkage but many basic nitrogens (NH2 becomes super highly positive charged, penetrate into gram negative bacteria)

- all basic nitrogens make this work (bind tightly to phosphates)

oxazolidinones

- fully synthetic

- oxazolidinones 5 membered ring with nitrogen and oxygen defines the structure (carbonyl = -one)

- linezolid

oxazolidinones - mechanism of action

- linezolid inhibited phage-specific in vitro translation, peptide chain termination and polypeptide chain elongation in a cell-free E. coli protein synthesis assay

- determined that it most likely binds 50S ribosomal subunit and prevents formation of a functional initiation complex

- other classes impact elongation

lincomycins

- isolated from Streptomyces

- lincomycin and clindamycin

- resemble macrolides in spectrum and MOA

- Cl in clinda is chloride (improved stability and activity)

- MOA similar to macrolides (bind ribosome and block elongation)

metabolic inhibitors: sulfonamides

blocked metabolic pathway needed for replication of nucleic acid of genome of bacteria

- Prontosil discovered to have antibiotic activity (1935) in vivo but not in vitro (2 nitrogens, from a dye)

- metabolized to sulfanilamide in the body

- Prontosil was a prodrug

sulfonamide SAR

- para-amino group essential – must be unsubstituted (R1=H or acyl tolerated) - para orientation

- aromatic ring and sulfonamide functional group essential and must be directly attached

- aromatic ring must be para-substituted only

- R2 is the only possible site for variations - other than that, limited SAR

- varying R2 affects plasma protein binding and solubility

mechanism of action of sulfa drugs

blocked folic acid pathway

- tetrahydrofolate = vitamin

- prokaryotes need to make folate (de novo folate synthesis)

- para-aminobenzoic acid looks similar to sulfonamide

- dihydropteroate synthetase makes dihydropteroate (we do not do this, we get it from our diet)

- if you increase dihydropteroate synthetase (target), it increases effectiveness of the drug

- suicide reaction, sulfonamide acts as a fake substrate (dead end product)

- over expression of DHPS - exhausts substrates of folate synthesis

crystal structure of DHPS bound to sulfanilamide

- pseudo substrate for that site

trimethoprim

- inhibits dihydrofolate reductase (folate biosynthesis) - no bonds, traditional competitive inhibitor

- antifolate (similar to sulfonamides)

- selective for bacterial DHFR

- bacteriostatic to bactericidal (kills bacteria, more powerful)

- sulfa and trimethoprim static agents used alone - cidal when used together (synergistic combination) - resistance pops up more slowly but still present

- specific for prokaryotic enzymes

- reflect small metabolites in the cell

- binds more strongly than folate, but cannot be reduced

- no activity against our enzyme

- good against E. coli and Staph aureus - UTIs --> always used as a combination (Bactrim)

dihydrofolate vs. tetrahydrofolate

- extra hydrogen on nitrogen

- reducing agent with NADPH = dihydrofolate reductase (adds hydrogen)

- target of trimethoprim

- accumulate more dihydrofolate and cannot reduce it = shuts the cell down

wild-type binding and a mutant

- changes in the enzyme active site for resistance - chromosomal mutations

- other dihydrofolate reductases and DHPS - bypass mechanisms that are resistant to the drug

- extensive resistance - may not longer be used

fluoroquinolones

- nalidixic acid was the first quinolone (synthesized 1962)

- quinolone ring (benzene, 6 membered ring, carbonyl) - fluorine always at that position

- Ciprofloxacin, Levofloxacin and Moxifloxacin most commonly used today - introduced a lot of basic nitrogen for gram-neg activity

- 1,3 dioxygen - similar to the tetracyclines, really good at binding metals (bind to target through Mg2+)

- cyclopropyl group further increased spectrum (also active against Gram-neg) - a lot of gram-pos activity

- used less because of side effects

fluoroquinolones MOA - revisited

- inhibit replication and transcription of bacterial DNA by stabilizing complex with DNA and topoisomerases (topoisomerases and gyrases relieve strand strain) - same pathway in bacteria and us but enough differences that we do not get cross reaction

- gram-pos bacteria: DNA and topoisomerase IV

- gram-neg bacteria: DNA and gyrase (required when helix is supercoiled after replication and transcription)

- cleave DNA, allow to unwind, the reattach it back together

- incompatible with antacids and any foods or supplements with Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+ - similar to tetracyclines

- resistance = mutations to gyrases, changes to drug uptake and efflux

fluoroquinolone (FQ) MOA

- (a) A ternary FQ/DNA/DNA gyrase complex leads to slow death of the bacteria

- (b) Formation of an FQ/topo IV/DNA ternary complex leads to more rapid bacterial cell death

- fragmented DNA

fluoroquinolone - resistance

- altered porins (gram-neg) that decrease uptake

- energy-dependent efflux (usually always)

- amino acid substitutions in gyrase and topoisomerase - reduce overall drug affinity (highest level of resistance)

next generation fluoroquinolones

- always include a bicyclic pyridinone system and carboxylic acid at C3

- delafloxacin more potent for gram positive but loses a lot of gram negative activity (super activity, retained more in bacteria than outside)

- developed to show activity against S. aureus, S. pneumoniae and resistant strains

- aniline cannot be protonated - only aniline nitrogen on delafloxacin (negative charge)

- zwitterionic = overall neutral but very charged on either side (helps with transport through porins)

retapamulin (2007)

belongs with protein synthesis inhibitors

- first antibiotic from the pleuromutilin class

- semi-synthetic derivative from a mushroom

- topical; effective against Gram-pos

- binds 50S subunit, inhibits protein synthesis

- low resistance profile