Sulfonamides and
Antimicrobial Antifolates
(Step 1)
Ehrlich was the father of anti-microbial chemotherapy and also
the father of immunology. He came up with the idea of a ‘magic
bullet’ that had a different toxicity for the parasite than for the
host. His principles for discovering anti-infectives included the
notion that synthetic compounds can cure infections, you need to
systematically explore structures and activities, you needed
standard infection models with reliable endpoints, you strive to
raise the therapeutic index (LD50/ED50), and that drug
resistance may arise in the pathogen against a class of chemicals
 He worked with arsenic and azo dyes, discovering the uses
of compounds like Salvarsan (agent 606 for syphilis), and
trypan red/blue or afridol for trypanosomiasis.
Gerhard Domagk thought dyes would potentially make
good drugs, since they bound proteins in wool. He
contributed to the discovery of Prontosil, the first highly
effective and reliably nontoxic antibacterial agent. Prontosil
is a sulfonamide (-SO2NH2).
It was determined that the Prontosil is metabolized to
Sulfanilamide (SA), its active form. SA was active both in
vitro and in vivo, and is produced from Prontosil by
metabolic activation in the tissues. Regardless of whether
SA or Prontosil is administered, patients excrete SA.
Sulfonamides structurally resemble PABA (paminobenzoic acid). Their mechanism involves the
inhibition of folic acid synthesis; they competitively inhibit
dihydropteroate synthetase by competing with PABA:
Pteridine + PO4 (pterin pyrophosphokinase)→ __ +
PABA (dihydropteroate synthetase)→ __ + glutamate →
dihydrofolate (dihydrofolate reductase)→ folate.
The most common way resistance arises is by mutation in the
dihydropteroate synthetase enzyme to escape the effects of
sulfonamides. Resistance may also arise from reduced
permeability to sulfonamides, increased expression of
dihydropteroate synthetase, or increases in PABA to outcompete
the sulfonamide.
Sulfonamides are selectively toxic against microbes because
they synthesize folic acid, whereas we cannot. We don’t have
the enzyme dihydropteroate synthetase. Furthermore, microbes
are impermeable to folic acid, so even if it were present in the
environment, they still wouldn’t take it up. We actively
transport folic acid.
Lots of derivatives have been synthesized, but only a dozen or
so have reached clinical use, and only three are now used.
Sulfanilamide is insoluble in the urine, and may result in
stones. Substituting at various locations on the molecule may
influence the antimicrobial spectrum, therapeutic index,
solubility, metabolic pattern, half life, permeability,
distribution, absorption, etc.
The sulfonamides presently in clinical use are Sulfisoxazole
(Gantrisin – most widely used), Sulfamethoxazole (Ganatol),
and Sulformethoxine (Sulfadoxine, Fanasil – 150 hour half
life, used sparingly).
Toxicity: Adverse reactions requiring cessation of therapy
are rare (3%), though in AIDS patients they are quite common.
They may include fever, rash, joint pain, and
lymphadenopathy. Very few of these reactions are dosedependent. Long acting sulfonamides may cause serious
Stevens-Johnson syndrome, so should only be administered for
good reasons.
Sulfonamides should NEVER be given to newborns. Very high
death rates were observed in premature infants treated with
sulfonamides. Deaths were associated with kernicterus, yellow
staining of the basal ganglia due to bilirubin deposits in the brain.
Sulfonamides bind to serum albumin and displace bilirubin from
being bound to the albumin. This leads to more free bilirubin, and
more gets into the brain and binds there. Total serum bilirubin
levels will be LOW, since a lot of it gets displaced and the
unbound form equilibrates with other body compartments.
Sulfonamides are cheap, orally bioavailable, and continue to be
used. They may be used for prophylaxis of simple urinary tract
infections from gram (-) bacteria. They are the drug of choice
for Nocardia, a genus of gram (+) bacteria. They may be used
for other things too.
Related compounds are used for leprosy (mycobacterium
leprae – Dapsone) and tuberculosis (p-aminosalcyclic acid –
PAS).
Many drugs are structurally related to sulfonamides. Some for
goiters, anti-diabetic agents, gout, acetazolamide (diuretic), etc.
Elion and Hitchings developed trimethoprim, as well as
mercaptopurine, pyrimethamine, acyclovir (antiviral), and
allopurinol (gout). These two studied purine and pyrimidine
synthesis, and spent a lot of time studying diaminopyrimidines.
Aminopterin and methotrexate are folic acid analogs, and they are
diaminopyrimidines.
Elion and Hitchings synthesized trimethoprim, which was a
highly effective antibacterial agent. It inhibits folate biosynthesis
at DHFR. Resistance to it may result from reduced susceptibility
to the drug, or less commonly over-production of DHFR. Both
humans and bacteria have DHFR, but trimethoprim is selective
for the bacterial DHFR. The human and bacterial versions are
different, even though they carry out the same reaction.
Trimethoprim toxicity is pretty rare. It may be
rash/nausea/vomiting. Or you can get folate deficiency in
nutritionally deprived patients, resulting in anemia,
thrombocytopenia, and neutropenia.
They then tried combination chemotherapy with both sulfonamides
and trimethoprim, and found a synergistic result. This
combination of trimethoprim and sulfamethoxazole was sold as
Bactrim/Co-trimoxazole. It had a broader spectrum of activity
than either drug alone, was less likely to have bacteria develop
resistance, less toxicity due to smaller doses of each drug, and is
bacteriocidal rather than bacteriostatic. It’s useful for UTIs, otitis
media, shigellosis, chronic bronchitis, pneumocystis carinii,
salmonella typhi, and MRSA.
Introduction to Antibacterials
An antibiotic is an antibacterial substance produced by a
microorganism. Basically drugs that kill or stop the growth of
bugs.
Individualizing therapy requires that you integrate clinical
medicine, microbiology and pharmacology related to the
particular infectious disease. Patients with the same underlying
problem may be very different and have different needs based
on the clinical syndrome, organism, appropriate drug class and
individual agent that best balances cost, convenience, side
effects, etc.
You begin with broad, empiric therapy. To do this, consider the
probability of different organisms given the clinical syndrome,
patient, and geographic factors (community vs. hospital
[nosocomial] acquired). Hospital acquired stuff is usually more
resistant and lethal. You should consider the lethality of possible,
but less probable, pathogens as well as local antibiotic sensitivity
patterns.
Eventually, you want to work toward a definitive therapy that is
narrower. You’d like to choose the best drug for the organism,
but also for the patient’s situation. This isn’t as dependent on
probabilities.
You want a narrow spectrum of coverage to avoid unnecessary
resistance, unnecessary adverse side effects, for simplicity of
management and to reduce cost of treatment.
There are lots of obstacles to choosing the right antibiotic. They
include syndromes caused by multiple agents and agents that cause
multiple syndromes, variations with population/geography/age,
agents may be unidentifiable by clinical findings, or simply not
knowing the cause of a syndrome. There are also so many
organisms and so many drugs, it’s tough to put it all together.
We should try to know, for a class of pathogens, the antibiotics
that incrementally cover them. And groups of organisms with
similar antibiotic sensitivities. Basically, know the grid.
More things to consider when choosing the right drug are:
mechanism of action, selective toxicity, spectrum of activity,
bacteriocidal/bacteriostatic, combination antibiotics, synergy vs.
antagonism between drugs.
The selective toxicity of an antibiotic is the relationship
between the toxicity in bacteria in relation to toxicity in the host.
Selective toxicity = bacterial toxicity / host toxicity. The
therapeutic window = host efficacy / host toxicity.
Selective toxicity is often due to the different biochemistry
between eukaryotes and prokaryotes. There are differences in
cell wall (cell wall active drugs), DNA gyrase (quinolones), RNA
polymerase (rifampin), ribosomes (ribosomal inhibitors), folate
synthesis/transport (sulfonamides), and dihydrofolate reductase
(trimethoprim).
Even though human and bacterial receptors may be only
distantly related, drugs that act on bacteria still produce a lot of
side effects in us.
The adverse effects are often unrelated to antimicrobial effects:
Β-lactams: CNS, bleeding, nephrotoxicity, allergy
Vancomycin: histamine release
Aminoglycosides: nephrotoxicity, ototoxicity, neuromuscular
Tetracyclines: discoloration of teeth and bones
Erythromycin: hepatitis, GI
Clindamycin: pseudomembranous colitis
Chloramphenicol: aplastic anemia, bone marrow
Quinolones: CNS toxicity, arthropathy, QTc prologation
Sulfonamides: hemolytic anemia
Trimethoprim: folate antagonism.
Bacteriocidal drugs kill the microorganisms. A bacteriostatic
drug alone (with immune dysfunction or in a sanctuary site
like the CNS) will prevent proliferation. A bacteriostatic
drug with good immune system and penetration will kill the
bugs as well. Generally, bacteriocidal drugs include
penicllins, cephalosporins, quinolones, aminoglycosides, and
trimethoprim/sulfamethoxazole. Bacteriostatic drugs include
tetracycline, macrolides, chloramphenicol, clindamycin,
sulfonamides, and trimethoprim.
The distinction is variable, with some drugs being cidal for
some microorganisms and static for others:
Macrolides: static against atypicals and GNR, cidal against S.
pyogenes and S. pneumoniae.
Chloramphenicol: static against S. aureus, cidal against S.
pneumoniae.
 Linezolid: static against Staphylococci and Enterococci, cidal
against Streptococci.
There are a lot of situations where either a bacteriocidal or
static agent may be appropriate.
 It may be good to use combinations of antibiotics for mixed
infections, preventing resistance (for TB since it’s particularly
prone to developing resistance), initial empiric therapy for a
serious infection, or for a synergistic effect (more than additive).
Synergy is pretty uncommon, an example might be penicillin and
aminoglycosides.
Antibiotic tissue penetration depends on all the usual stuff
(concentration, size, protein binding, transport, etc), but also
inflammation. Inflammation may make a membrane more
permeable for some drugs. But for β-lactams, pumps that remove
the drug from the CNS are less active in inflammation. So these
drugs accumulate in the CNS during inflammation.
The extravascular characteristics may also alter drug
concentrations. If there’s a large reservoir, big changes in
serum concentration may only manifest as small changes in
the tissues. Or, if a tissue has pumps getting rid of the drug,
extravascular concentrations of the drug may be quite low
regardless of serum concentrations
Loading doses may be used to rapidly achieve a target
concentration.
Various drugs have different distributions to the CNS, urine
and other compartments. In the CNS, penicillin has medium
penetration (1% normally, but 5% with inflammation).
Barriers to drug penetration include the outer membrane of
gram (-) bacteria, cell walls, periplasmic beta-lactamases, the
cytoplasmic membrane, and cytoplasmic pumps.
The time course of a drug often doesn’t parallel the time course
of its effect. Some drugs’ effects are concentration dependent
(quinolone, aminoglycosides, tetracycline), but others are not and
may be time dependent (beta-lactam, vancomycin, oxazolidinone,
macrolides, clindamycin). For time dependent ones, as long as
the concentration is >4xMIC, increasing the concentration gives
no greater effect.
Many also exhibit a Post Antibiotic Effect (PAE), in which
cidal/static properties continue after a short exposure to the drug.
Beta lactam antibiotics exhibit PAE against gram (+) organisms,
but not gram (-) ones. Aminoglycosides and quinolones show
PAE vs. gram (-) organisms.
Cell Wall Inhibitors
Gram (+) bacteria have a surface of thick peptidoglycan,
with some teichoic acid, overlaying the plasma membrane.
Gram (-) bacteria have an outer membrane with LPS (may
act as a barrier for some drugs), a periplasmic space with a
single layer of peptidoglycan, and an inner membrane.
The peptidoglycan of the cell wall is made of chains of
alternating NAG and NAM, which are cross-linked by peptide
bridges. Gram (-) rods have a modified amino acid, DAP,
followed by d-Ala d-Ala. Gram (+) cocci have a lysine with a
pentaGlycine followed by d-Ala d-Ala. Cross linking occurs at
these residues just before the d-Ala d-Ala.
Transglycosidase joins NAGs and NAMs, and transpeptidase
cross-links strands of NAG/NAM. Several other enzymes act to
lay down peptidoglycan. In the process of producing
peptidoglycan, you have to break down and displace some of the
existing layer. So there’s continually new wall being synthesized
and broken apart.
The d-Ala d-Ala sequence is targeted by transpeptidase for
cross-link formation. D-Ala isn’t present in vertebrates. The
terminal d-Ala is cleaved, and the remaining one forms a
covalent complex with the enzyme. This covalent bond to the dAla is then replaced with the peptide bond cross-link to another
chain of peptidoglycan.
The beta-lactam ring of penicillin and other beta-lactam
antibiotics holds these molecules in a conformation that is
homologous to the d-Ala d-Ala on which transpeptidase acts.
Penicillin inhibits transpeptidation by forming a covalent
complex with the enzyme. Autolysins (peptidoglycan
hydrolases) continue to dissolve the cell wall, and since it’s not
being synthesized the wall becomes depleted. In a way, the
bacteria’s own enzymes destroy it.
The enzymes that bind penicillin and are involved in
peptidoglycan synthesis and remodeling are called penicillin
binding proteins (PBPs - transpeptidase, transglycosylase, etc).
They may have various specific functions, like elongating the
cell, maintaining shape, forming septa, etc. Their sensitivities to
beta-lactam antibiotics also varies, and not all PBP inhibition is
lethal.
Beta lactam antibiotics can cause significant morphological
changes in the microbes they affect, due to alteration of cell wall
parameters.
These antibiotics have selective toxicity (toxic for bacteria
more than us) because bacteria have cell walls, d-Ala d-Ala, and
transpeptidease whereas we do not.
Penicillin G:
 Acts on gram (+) Strep as well as oral (above-the-belt)
anaerobes. When it first came out it was effective against most
microorganisms, but resistance has changed that.
 It is acid unstable and erratically absorbed, so you can’t take it
orally.
It’s distributed into 50% of the body weight, and has poor
penetration into the CSF due to an organic anion transport (OAT)
pump. Inflammation inhibits the pump and increases penetration
into the CSF.
Only 10% of it gets metabolized, but some of the products
may be allergenic.
It has a very short half life of 45 minutes, and is excreted by
the kidneys through glomerular filtration and secretion by an
organic anion pump. Probenecid inhibits this pump and lowers
the excretion rate.
 Beta-lactam antibiotics are bactericidal, have timedependent killing (the more time you spend over the MIC, the
more you kill), and have a post antibiotic effect (PAE) for gram
(+) bacteria. The PAE is suppression of bacterial growth that
persists after short exposure of organisms to antimicrobial
agents. It allows dosing to be less frequent that suggested by
the half life.
Resistance to penicillin may arise by alterations in penicillin
binding protein sites, reduced permeability of the drug, or
production of beta-lactamase to degrade the antibiotic by
opening its beta-lactam ring. Beta-lactamase is plasmid
mediated, and this enzyme is excreted. It is constitutively
expressed and present in the periplasm in many gram (-)
bacteria. To counter this, we have developed beta-lactamase
inhibitors: Clavulanate, Sulbactam, Tazobactam.
Clavulanate competes with penicillin for access to the betalactamase active site, and the beta-lactam ring of clavulanate is
opened instead of penicillin’s.
Augmentin = clavulanate + amoxicillin. Much more potent that
amoxicillin alone.
 Beta-lactamase inhibitors have limitations. These include
activity against only class A serine hydroxylases, though
tazobactam is active against other classes. Also, the inhibitor is
degraded after binding. Some resistance has emerged, and
multiple classes of beta-lactamase may be produced by one
organism (or multiple organisms present may result in the
presence of several beta-lactamases). Finally, clavulanate
induces beta-lactamase expression, which is counterproductive.
Future development will be focusing on expanding the classes of
enzymes on which the drugs will work, as well as increasing
membrane permeability.
Adverse effects of penicillin include
Hypersensitivity (any type may occur, but type I is rare/lifethreatening). The most common toxic side effect is GI symptoms
with oral drugs. Ticarcillin may result in a sodium overload.
Rarely, you may see bone marrow depression, hepatitis, platelet
aggregation, or seizures.
If someone has a history of type I anaphylactic reaction to
penicillin, they’ll give a skin test before administering a beta
lactamase antibiotic. If the skin test is positive, 50-70% of
patients will experience anaphylaxis with penicillin. A positive
skin test will also be cross-reactive against cephalosporin 30% of
the time. If the test is negative, only 1-3% will have minor
cutaneous reactions which aren’t a big deal.
Drawbacks of penicillin include its short half-life, instability
in gastric acid, inactivation by beta-lactamase, poor treatment
of gram (-) bacteria, and its allergenicity.
 You can modify penicillin side chains to try to increase its
stability against beta-lactamases, increase its binding to PBPs,
alter its pharmacokinetics, make it more acid stable, or make it
more permeable to gram (-) bacteria.
Derivatives of penicillin have been made to increase its
spectrum against gram (-)s (amoxicillin, ampicillin, ticarcillin and
pipercillin), improve its pharmacokinetic parameters (penicillin
V, penicillin G benzathine/procaine), and be resistant to
penicillinases (methicillin, oxacillin, cloxacillin, dicloxacillin).
Longer acting penicillins like procaine penicillin, benzathine
penicillin (very slow!) and orally available penicillin V made the
half life longer. Benzathine penicillin is good against syphilis,
because you need a really low dose for a long time, and it gives
just that.
Aminopenicillins:
Ampicillin acts on some gram (-) bacteria including H.
influenza, it is 50% orally bioavailable, and it doesn’t cause
allergy (though it does cause diarrhea and rash). Combining
these with a beta-lactamase inhibitor can be very effective
against beta-lactamase producing Staph, Neisseria, and H.
influenza. Amoxicillin + clavulanate = Augmentin (oral).
Acts on gram (+) Pneumococcus, Streptococcus, and
Enterococcus. Acts on gram (-) H. influenzae, E. coli, Proteus
mirabilis, and Salmonella.
 Augmentin increases spectrum to include beta-lactamase
producing S. aureus, H influenzae, M catarrhalis and many gram
(-) rods.
Amoxicillin is 100% orally bioavailable. Combining these with
a beta-lactamase inhibitor can be very effective against betalactamase producing Staph, Neisseria, and H. influenza.
Ampicillin +sulbactam = Unasyn (IV).
Antipseudomonal aminoacylpenicillins: piperacillin,
piperacillin/tazobactam, mezlocillin, azlocillin.
o Piperacillin covers what ampicillin does, but also more
nosocomial (class II gram (-) rods), Pseudomonas aeruginosa,
Bacteroides fragilis. Tazobactam extends coverage to betalactamase producing strands of staphylococci and many GNR,
though it’s no better against pseudomonas than piperacillin
alone since pseudomonas doesn’t use beta-lactamase. The
combo is used for serious gram (-) infections.
Ticarcillin shows time dependent killing. In this situation, a
continuous infusion could be used to avoid falling below a
minimum or rising above a maximum desired concentration.
Continuous infusion actually showed better results than
intermittent dosing too.
Gram (+) bacteria produce “penicillinase” which is basically
the same as beta-lactamase from gram (-) bacteria. Penicillinase
resistant penicillins include methicillin, oxacillin, cloxacillin,
dicloxacillin, and nafcillin. MRSA isn’t resistant to the
antibiotics because of beta-lactamase, rather due to altered PBPs,
so it’s also resistant to all beta-lactam antibiotics.
These penicillinase resistant penicillins are active against
penicillinase producing Staphylococci, Pneumococci, and group A
Streptococci.
 Staph aureus and epidermidis (MRSA and MRSE) are resistant
to these. They are also resistant to cephalosporins and imipenem.
 Dorothy Hodgkin figured out the structure of penicillin.
Pharmacokinetics of penicillins: Generally (except
ceftriaxone) they have short half lives, renal clearance
predominates, and have variable protein binding. Their
distribution is poor to the eye, brain, CSF and prostate, and
inflammation usually enhances penetration.
Dosing: despite half life of .5-1.5 hours, you can dose every 4
hours because of the PAE. The exceptions are for meningitis you
want every 2 hours, amoxicillin only needs to be given every 8
hours, and benzathine and procaine penicillin have very long half
lives.
Penicillins are one class of beta-lactam antibiotics. Another is
the cephalosporins. They also have a beta-lactam ring, they
have a broad spectrum of activity [gram (+/-) and
pseudomonas], they are resistant to beta-lactamases, and are
safer than penicillins. There are four ‘generations’ of
cephalosporins based on their spectrum of activity.
Generations progressively increase in their coverage of gram
(-) bacteria.
1st: cephazolin, cephalothin, cephalexin - good for strep and
staph aureus.
2nd: cefotetan – better gram (-) coverage, a little worse gram
(+). Surgeons use a lot, good for Bacteroides fragilis and
interabdominal infections.
 3rd: ceftriaxone, ceftazidime – even better gram (-) coverage.
3rd/4th: cefepime – more resistant to some beta-lactamases.
Cephalosporins show PAE against gram (+) organisms. They
are characterized by time dependent killing, so continuous
infusion is better.
Adverse effects of cephalosporins include hypersensitivity and
anaphylaxis (same as penicillin, but not as common).
Unique cephalosporins: Ceftriaxone (3rd gen) can be given
once daily, whereas most are 3x daily. Cefotetan (2nd gen) is
particularly good at battling anaerobes. Cefepime (4th gen) is
particularly potent against pseudomonas.
A third group of beta-lactam antibiotics are the carbapenems.
These include meropenem and imipenem/Cilastatin.
Pseudomonas have a protein in their outer membrane just for the
drugs in this class, and allows the drugs to get in. In some cases,
these pores are the only way for drugs to get into these gram (-)
bacteria.
They have a broad spectrum. They kill gram (+)s except
Enterococcus faecium and MRSA. They kill gram (-)s including
pseudomonas. They also kill anaerobes. And, so far resistance to
them is rare.
They have a PAE for gram (-) and (+) bacteria.
Carbapenems are associated with seizures, though the
incidence isn’t well defined.
Meropenem has a 1 hour half life, but can be given every 8
hours due to PAE. It is also metabolized in the kidneys, in
addition to being filtered and secreted there. Proximal tubular
dehydropeptidase I hydrolyzes the meropenem in the urine.
The metabolite is a renal tubular toxin, though, so it’s often
administered with Cilastatin to inhibit the renal
dehydropeptidase I. This allows more of the meropenem itself
to be excreted.
Aztreonam has only gram (-) coverage with no crossallergenicity with penicillins, so you can use it without fear of
anaphylaxis. It’s also a non-aminoglycoside.
Vancomycin is a huge molecule, and it only works on gram (+)
bacteria. It H-bonds with the d-Ala d-Ala and pentaglycine of
gram (+) peptidoglycan so that transpeptidases can’t link them
together. Some Enterococci are vancomycin resistant. Resistance
may arise by changing d-Ala d-Ala to d-Ala d-Lac.
Vancomycin enters the CSF poorly with uninflamed meninges,
but improves with inflammation. There is little metabolism of it.
It is excreted renally. Half life is usually around 6 hours. Its
killing is time dependent.
 Vancomycin toxicity includes allergenicity (drug fever, rash, not
anaphylaxis), phlebitis, and red man flushing with a rapid IV dose.
No good evidence for oto or nephrotoxicity.
Ribosomal Inhibitors
The prokaryotic ribosome is a complex of protein and RNA. All
together it is 70S, and it includes a 50S subunit and a 30S
subunit. tRNA may bind to an A-site, P-site, or E-site. There is a
peptidyl transferase cavity where the main reaction occurs; lots of
drugs act here. There is also a peptide exit tunnel where the
elongating chain sits.
Polypeptide elongation: empty tRNA is in the E-site, tRNApolypeptide is in the P-site and exit tunnel. A tRNA/AA halfenters the A-site (A/T), then fully enters (A/A). The polypeptide
is moved to the tRNA in the A-site. The empty tRNA leaves the
E site, and the remaining tRNAs shift (P/E and A/P). Then they
fully shift to the E-site (E/E) and P-site (P/P).
Gentamicin (aminoglycoside): bacteriocidal, acts at the 30S Asite. Blocks initiation, terminates, and causes misreads.
Tetracycline: bacteriostatic, acts at the 30S A-site. Blocks
tRNA binding (A/T to A/A)
Chloramphenicol: bacteriostatic, acts at the 50S A-site. Blocks
peptidyl transferase.
Clindamycin: bacteriostatic, acts at the 50S A and P sites.
Blocks peptidyl transferase.
Linezolid (Oxazolidinone): bacteriostatic, acts at the 50S Psite. Blocks fMet rTNA initiation complex.
Erythromycin (Macrolide): bacteriostatic, acts at the 50S exit
site. Blocks the peptide exit tunnel.
Aminoglycoside antibiotics (Gentamicin, Tobramycin,
Amikacin) all have 3 hexose sugars linked by O-glycosidic
linkages and one or more amino groups. They can act by
allowing mismatched codon/anticodon pairs to bind with high
affinity and incorporate the wrong amino acid. They may also
act by premature termination and breaking apart the ribosome,
or blocking initiation.
These bind the 30S subunit at the A site. The aminoglycoside
antibiotics are actively transported into bacteria through an illicit
polyamine transporter, accumulate, and are retained there.
Aminoglycosides are inhibited by chloramphenicol
(antagonist), anaerobic environments, and acid. They show
synergy when used with beta-lactams (good against Enterococci
or S. aureus)