Antimicrobial Agents in the Treatment of Infectious Disease
(This chapter has 6 pages)
© Kenneth Todar, PhD
Antimicrobial Agents Used in the Treatment
Examination of the foregoing table reveals that there are a
of fundamental ways that antibacterial antibiotics work as therapeutic
agents. Recall that the target of an antibiotic should be unique to the
bacterium and not found, or not accessible to the antibiotic, in the
patient. These are the most important targets in bacteria that have
been exploited so far.
1. Attack bacterial cell wall synthesis. Bacteria have murein in their
cell walls, not found in the host, and murein (peptidoglycan) is
essential to the viability of the bacterium.
2. Interfere with protein synthesis. Attack is almost always ate the
level of translation using 70S ribosomes in the translation machinery.
70S cytoplasmic ribosomes are absent in eucaryotes.
3. Interference with nucleic acid synthesis (RNA and DNA), which
exploits differences between RNA polymerases and DNA replication
strategies in bacteria and eucaryotes.
4. Inhibition of an essential metabolic pathway that exists in the
bacterium but does not exist in the host. This is usually brought about
through the use of competitive chemical analogs for bacterial enzymatic
5. Membrane inhibition or disruption doesn't work too well because of
the similarities between eucaryotic and bacterial membranes. However,
the outer membrane of Gram-negative bacteria is a reasonable point of
attack and some membrane inhibitors are included in the discussion
Cell wall synthesis inhibitors
Cell wall synthesis inhibitors generally inhibit some step in the
synthesis of bacterial peptidoglycan. They exert their
selective toxicity against bacteria because humans cells lack cell
Beta lactam antibiotics. Chemically, these antibiotics
4-membered beta lactam ring. They are the products of two genera of
fungi, Penicillium and Cephalosporium, and are
correspondingly represented by the penicillins and cephalosporins.
Chemical structures of some
beta-lactam antibiotics. Clockwise: penicillin, cephalosporin,
monobactam, carbapenem. Note the characteristic structure of the beta
The beta lactam antibiotics are stereochemically related to
D-alanyl-D-alanine, which is a substrate for the last step in
peptidoglycan synthesis, the final cross-linking between between
peptide side chains. Penicillins bind to
and inhibit the carboxypeptidase and transpeptidase enzymes that are
required for this step in peptidoglycan biosynthesis. Beta lactam
antibiotics are bactericidal and require that cells be
actively growing in order to exert their toxicity.
Different beta lactams differ in their spectrum of activity and
on Gram-negative rods, as well as their toxicity, stability in the
body, rate of clearance from blood, whether they can be taken orally,
to cross the blood-brain barrier, and susceptibility to bacterial
Natural penicillins, such as penicillin G or penicillin
V (benzyl penicillin), are produced by fermentation of Penicillium
They are effective against streptococci, gonococci and
staphylococci, except where resistance has developed. They are
considered narrow spectrum since they are not effective against
(Benzylpenicillin) is typically given by parenteral administration
because it is unstable in the acid of the stomach. However, this
achieves higher tissue concentrations than orally-administered
penicillins and this increases its antibacterial potential.
"PenG" may be used in treatment of bacterial endocarditis, gonorrhea,
syphilis, meningitis, and pneumonia.
Semisynthetic penicillins first appeared in 1959. A mold
produces the main part of the molecule (6-aminopenicillanic acid),
can be modified chemically by the addition of side chains. Many of
these compounds have been developed to have distinct benefits or
advantages over penicillin G, such as increased spectrum of activity
(effectiveness against Gram-negative rods), resistance to
penicillinase, effectiveness when administered orally, etc.; amoxicillin
and ampicillin have broadened spectra against Gram-negative
and are effective orally; methicillin is
The semisynthetic beta-lactam, amoxicillin. Amoxicillin is usually the
drug of choice within the class because it is better absorbed following
oral administration than other beta-lactam antibiotics. It is
susceptible to degradation by bacterial beta-lactamase enzymes so it
may be given with calvulanic acid (below) to decrease its
susceptibility. It is used against a wide range of Gram-positive
bacteria, including Streptococcus
Streptococcus pneumoniae, non beta-lactamase producing strains
of Staphylococcus aureus and Enterococcus faecalis. Susceptible
Gram-negative organisms include non beta-lactamase producing strains of
Haemophilus influenzae, Neisseria
gonorrhoeae and N.
Clavulanic acid is a chemical sometimes added to a
semisynthetic penicillin preparation. Thus, amoxicillin plus
clavulanate is clavamox or augmentin. The clavulanate
is not an antimicrobial agent. It inhibits beta lactamase enzymes and
has given extended life to penicillinase-sensitive beta lactams.
The structure of calvulanic
acid. Clavulanic acid is not an antibiotic. It is a beta-lactamase
inhibitor sometimes combined with semisynthetic beta lactam antibiotics
to overcome resistance in bacteria that produce beta-lactamase enzymes,
which otherwise inactivate the antibiotic. Most commonly it is combined
with amoxicillin (above) as Augmentin (trade name) or the veterinary
Although nontoxic, penicillins occasionally cause death when
administered to persons who are allergic to them. In the U.S. there are
300 - 500 deaths annually due to penicillin allergy. In allergic
individuals the beta lactam molecule attaches to a serum protein and
initiates an IgE-mediated inflammatory response.
Cephalosporins are beta lactam antibiotics with a similar
mode of action to penicillins. They are produced by species of
Cephalosporium molds. The have
a low toxicity and a somewhat broader spectrum
than natural penicillins. They are often used as penicillin
substitutes against Gram-negative bacteria and in surgical
prophylaxis. They are subject to degradation by some bacterial
beta-lactamases, but they tend to be resistant to beta-lactamases from S.
The core structure of
cephalosporin. Substituent groups added at position X
on the six-membered ring
generates variants of the antibiotic.
Two other classes of beta lactams are the carbapenems and monobactams.
The latter are particularly useful for the treatment of allergic
individuals. A person who becomes allergic to penicillin usually
becomes allergic to the cephalosporins and the carbapenems as well.
Such individuals can still be treated with the monobactams, which are
structurally different so as not to induce allergy.
Aztreonam is a synthetic monocyclic beta lactam antibiotic (a
monobactam) originally isolated from the bacterium Chromobacterium violaceum. It
is not useful against Gram-positive bacteria but it has strong activity
against a wide range of susceptible Gram-negative bacteria, including Pseudomonas aeruginosa, E. coli,
Haemophilus and Klebsiella.
Bacitracin is a polypeptide antibiotic produced by Bacillus
species. It prevents cell wall growth by inhibiting the release of
the muropeptide subunits of peptidoglycan from the lipid carrier
molecule that carries the
subunit to the outside of the membrane. Teichoic acid synthesis, which
the same carrier, is also inhibited. Bacitracin has a high toxicity
precludes its systemic use. It is present in many topical antibiotic
and since it is not absorbed by the gut, it is given to "sterilize" the
prior to surgery.
Bacitracin is a polypeptide antibiotic produced by the licheniformis
group of Bacillus subtilis var.
Tracy. It is effective used topically, primarily against Gram-positive
bacteria. It is used in ointment or cream form for topical treatment of
a variety of localized skin and eye infections, as well as for the
prevention of wound infections. A popular brand name Neosporin,
bacitracin, neomycin and polymyxin B.
Cycloserine inhibits the early stages of murein synthesis
where D-alanyl-D-alanine is added to the growing peptide side chain.
The antibiotic resembles D-alanine in spatial structure, and it
competitively inhibits the racemase reaction that converts L-alanine to
D-alanine and the synthetase reaction that joins two D-alanine
molecules. The affinity of cycloserine for these enzymes is about a
hundred times greater than that of D-alanine. Cycloserine enters
bacterial cells by means of an active transport system for glycine and
can reach a relatively high intracellular concentration. This
concentrating effect, along with its high affinity for susceptible
enzymes, enables cycloserine to function as a very effective
antimicrobial agent. However, it is fairly toxic and has limited use as
a secondary drug for tuberculosis.
Cycloserine is an oral broad spectrum
antibiotic effective against tuberculosis,
by inhibiting cell wall synthesis of TB bacilli at the early stages
peptidoglycan synthesis. For the treatment against tuberculosis, it is
classified as a second line drug.
Glycopeptides, such as the antibiotic vancomycin,
inhibit both transglycosylation and transpeptidation
reactions during peptidoglycan assembly. They bind to the muropeptide
subunit as it is transferred out of the cell cytoplasm and inhibit
subsequent polymerization reactions. Vancomycin is not effective
against Gram-negative bacteria because it cannot penetrate their outer
membrane. However, it has become important in clinical usage for
treatment of infections by strains of Staphylococcus aureus
that are resistant to virtually all other antibiotics (MRSA).
is a glycopeptide antibiotic used in the prophylaxis and treatment of
infections caused by Gram-positive bacteria. It has traditionally been
reserved as a drug of "last resort",
used only after treatment with other antibiotics had failed, although
the emergence of vancomycin-resistant organisms means that it is
increasingly being displaced from this role by linezolid and the
Cell membrane inhibitors
These antibiotics disorganize the structure or inhibit the function
of bacterial membranes. The integrity of the cytoplasmic and outer
membranes is vital to bacteria, and compounds that disorganize the
membranes rapidly kill the cells. However, due to the similarities in
phospholipids in eubacterial and eucaryotic membranes, this action is
rarely specific enough to permit these compounds to be used
systemically. The only antibacterial antibiotics of clinical importance
that act by this mechanism are the polymyxins, produced
by Bacillus polymyxa. Polymyxin is effective mainly against
bacteria and is usually limited to topical usage. Polymyxins bind to
membrane phospholipids and thereby interfere with membrane function.
Polymyxin is occasionally given for urinary tract infections caused by Pseudomonas
strains that are gentamicin, carbenicillin and tobramycin resistant.
The balance between effectiveness and damage to the kidney and other
is dangerously close, and the drug should only be given under close
supervision in the hospital.
Polymyxins are cationic detergent antibiotics, with a general structure
of a cyclic peptide with a long hydrophobic tail. They disrupt the
structure of the bacterial cell membrane by interacting with its
phospholipids. Polymyxins have a bactericidal effect on Gram-negative
bacilli, especially on Pseudomonas and coliform bacteria. Polymyxin
antibiotics are highly neurotoxic and nephrotoxic, and very poorly
absorbed from the gastrointestinal tract. Polymyxins also have