Color Atlas of Pharmacology (Part 23): Antibacterial Drugs

Antibacterial Drugs
Drugs for Treating Bacterial Infections
When bacteria overcome the cutaneous
or mucosal barriers and penetrate body
tissues, a bacterial infection is present.
Frequently the body succeeds in remov-
ing the invaders, without outward signs
of disease, by mounting an immune re-
sponse. If bacteria multiply faster than
the body’s defenses can destroy them,
infectious disease develops with inflam-
matory signs, e.g., purulent wound in-
fection or urinary tract infection. Appro-
priate treatment employs substances
that injure bacteria and thereby prevent
their further multiplication, without
harming cells of the host organism (1).
Apropos nomenclature: antibiotics
are produced by microorganisms (fungi,
bacteria) and are directed “against life”
at any phylogenetic level (prokaryotes,
eukaryotes). Chemotherapeutic agents
originate from chemical synthesis. This
distinction has been lost in current us-
age.
Specific damage to bacteria is partic-
ularly practicable when a substance
interferes with a metabolic process that
occurs in bacterial but not in host cells.
Clearly this applies to inhibitors of cell
wall synthesis, because human and ani-

mal cells lack a cell wall. The points of
attack of antibacterial agents are sche-
matically illustrated in a grossly simpli-
fied bacterial cell, as depicted in (2).
In the following sections, polymyx-
ins and tyrothricin are not considered
further. These polypeptide antibiotics
enhance cell membrane permeability.
Due to their poor tolerability, they are
prescribed in humans only for topical
use.
The effect of antibacterial drugs can
be observed in vitro (3). Bacteria multi-
ply in a growth medium under control
conditions. If the medium contains an
antibacterial drug, two results can be
discerned: 1. bacteria are killed—bacte-
ricidal effect; 2. bacteria survive, but do
not multiply—bacteriostatic effect. Al-
though variations may occur under
therapeutic conditions, different drugs
can be classified according to their re-
spective primary mode of action (color
tone in 2 and 3).
When bacterial growth remains un-
affected by an antibacterial drug, bacte-
rial resistance is present. This may oc-
cur because of certain metabolic charac-
teristics that confer a natural insensitiv-
ity to the drug on a particular strain of

bacteria (natural resistance). Depending
on whether a drug affects only a few or
numerous types of bacteria, the terms
narrow-spectrum (e.g., penicillin G) or
broad-spectrum (e.g., tetracyclines)
antibiotic are applied. Naturally sus-
ceptible bacterial strains can be trans-
formed under the influence of antibac-
terial drugs into resistant ones (acquired
resistance), when a random genetic al-
teration (mutation) gives rise to a resist-
ant bacterium. Under the influence of
the drug, the susceptible bacteria die
off, whereas the mutant multiplies un-
impeded. The more frequently a given
drug is applied, the more probable the
emergence of resistant strains (e.g., hos-
pital strains with multiple resistance)!
Resistance can also be acquired
when DNA responsible for nonsuscepti-
bility (so-called resistance plasmid) is
passed on from other resistant bacteria
by conjugation or transduction.
266 Antibacterial Drugs
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Antibacterial Drugs 267
A. Principles of antibacterial therapy
Selective
antibacterial

toxicity
Bacteria
Body cells
Cell
membrane
Cell wall
Bacterium
DNA RNA
Protein
1 day
Antibiotic
Insensitive strain
Sensitive strain with
resistant mutant
Selection
3.
2.
1.
Immune
defenses
Anti-
bacterial
drugs
Bacterial
invasion:
infection
Penicillins
Cephalosporins
"Gyrase-inhibitors"
Nitroimidazoles

Bacitracin
Vancomycin
Polymyxins
Tyrothricin
Rifampin
Tetracyclines
Chloramphenicol
Erythromycin
Clindamycin
Aminoglycosides
Sulfonamides
Trimethoprim
Tetrahydro-
folate
synthesis
Resistance
Bacteriostatic
Bactericidal
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Inhibitors of Cell Wall Synthesis
In most bacteria, a cell wall surrounds
the cell like a rigid shell that protects
against noxious outside influences and
prevents rupture of the plasma mem-
brane from a high internal osmotic
pressure. The structural stability of the
cell wall is due mainly to the murein
(peptidoglycan) lattice. This consists of
basic building blocks linked together to

form a large macromolecule. Each basic
unit contains the two linked aminosug-
ars N-acetylglucosamine and N-acetyl-
muramyl acid; the latter bears a peptide
chain. The building blocks are synthe-
sized in the bacterium, transported out-
ward through the cell membrane, and
assembled as illustrated schematically.
The enzyme transpeptidase cross-links
the peptide chains of adjacent amino-
sugar chains.
Inhibitors of cell wall synthesis
are suitable antibacterial agents, be-
cause animal and human cells lack a cell
wall. They exert a bactericidal action on
growing or multiplying germs. Mem-
bers of this class include !-lactam anti-
biotics such as the penicillins and cepha-
losporins, in addition to bacitracin and
vancomycin.
Penicillins (A). The parent sub-
stance of this group is penicillin G (ben-
zylpenicillin). It is obtained from cul-
tures of mold fungi, originally from Pen-
icillium notatum. Penicillin G contains
the basic structure common to all peni-
cillins, 6-amino-penicillanic acid (p.
271, 6-APA), comprised of a thiazolidine
and a 4-membered !-lactam ring. 6-
APA itself lacks antibacterial activity.

Penicillins disrupt cell wall synthesis by
inhibiting transpeptidase. When bacte-
ria are in their growth and replication
phase, penicillins are bactericidal; due
to cell wall defects, the bacteria swell
and burst.
Penicillins are generally well toler-
ated; with penicillin G, the daily dose
can range from approx. 0.6 g i.m. (= 10
6
international units, 1 Mega I.U.) to 60 g
by infusion. The most important ad-
verse effects are due to hypersensitivity
(incidence up to 5%), with manifesta-
tions ranging from skin eruptions to
anaphylactic shock (in less than 0.05% of
patients). Known penicillin allergy is a
contraindication for these drugs. Be-
cause of an increased risk of sensitiza-
tion, penicillins must not be used local-
ly. Neurotoxic effects, mostly convul-
sions due to GABA antagonism, may oc-
cur if the brain is exposed to extremely
high concentrations, e.g., after rapid i.v.
injection of a large dose or intrathecal
injection.
Penicillin G undergoes rapid renal
elimination mainly in unchanged form
(plasma t
1/2

~ 0.5 h). The duration of
the effect can be prolonged by:
1. Use of higher doses, enabling plas-
ma levels to remain above the minimal-
ly effective antibacterial concentration;
2. Combination with probenecid. Re-
nal elimination of penicillin occurs
chiefly via the anion (acid)-secretory
system of the proximal tubule (-COOH
of 6-APA). The acid probenecid (p. 316)
competes for this route and thus retards
penicillin elimination;
3. Intramuscular administration in
depot form. In its anionic form (-COO
-
)
penicillin G forms poorly water-soluble
salts with substances containing a posi-
tively charged amino group (procaine,
p. 208; clemizole, an antihistamine;
benzathine, dicationic). Depending on
the substance, release of penicillin from
the depot occurs over a variable inter-
val.
268 Antibacterial Drugs
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Antibacterial Drugs 269
A. Penicillin G: structure and origin; mode of action of penicillins; methods
for prolonging duration of action

Bacterium
Cell wall
Cell membrane
Cell wall
building block
Amino acid
chain
Cross-linked
by
transpeptidase
Sugar
Penicillin G
Fungus
Penicillium notatum
Human
Penicillin
allergy
Neurotoxicity
at very
high dosage
Plasma concentration
3 x Dose
Minimal
bactericidal
concentration
Time
Increasing the dose
Anion
secretory
system

Combination with probenecid Depot preparations
~1
~7-28
~2
Inhibition of
cell wall synthesis
Probenecid
Penicillin
Pr
ocaine
Penicillin
+
-
Clemizole
Penicillin
+
-
Benzathine
2 Penicillins
+
-
+
Duration of action (d)
Antibody
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Although very well tolerated, peni-
cillin G has disadvantages (A) that limit
its therapeutic usefulness: (1) It is inac-
tivated by gastric acid, which cleaves

the !-lactam ring, necessitating paren-
teral administration. (2) The !-lactam
ring can also be opened by bacterial en-
zymes (!-lactamases); in particular,
penicillinase, which can be produced by
staphylococcal strains, renders them re-
sistant to penicillin G. (3) The antibacte-
rial spectrum is narrow; although it en-
compasses many gram-positive bacte-
ria, gram-negative cocci, and spiro-
chetes, many gram-negative pathogens
are unaffected.
Derivatives with a different sub-
stituent on 6-APA possess advantages
(B): (1) Acid resistance permits oral ad-
ministration, provided that enteral ab-
sorption is possible. All derivatives
shown in (B) can be given orally. Penicil-
lin V (phenoxymethylpenicillin) exhib-
its antibacterial properties similar to
those of penicillin G. (2) Due to their
penicillinase resistance, isoxazolylpen-
icillins (oxacillin dicloxacillin, flucloxacil-
lin) are suitable for the (oral) treatment
of infections caused by penicillinase-
producing staphylococci. (3) Extended
activity spectrum: The aminopenicillin
amoxicillin is active against many gram-
negative organisms, e.g., coli bacteria or
Salmonella typhi. It can be protected

from destruction by penicillinase by
combination with inhibitors of penicilli-
nase (clavulanic acid, sulbactam, tazo-
bactam).
The structurally close congener am-
picillin (no 4-hydroxy group) has a simi-
lar activity spectrum. However, because
it is poorly absorbed (<50%) and there-
fore causes more extensive damage to
the gut microbial flora (side effect: diar-
rhea), it should be given only by injec-
tion.
A still broader spectrum (including
Pseudomonas bacteria) is shown by car-
boxypenicillins (carbenicillin, ticarcillin)
and acylaminopenicillins (mezclocillin,
azlocillin, piperacillin). These substanc-
es are neither acid stable nor penicilli-
nase resistant.
Cephalosporins (C). These !-lac-
tam antibiotics are also fungal products
and have bactericidal activity due to in-
hibition of transpeptidase. Their
shared basic structure is 7-aminocepha-
losporanic acid, as exemplified by
cephalexin (gray rectangle). Cephalo-
sporins are acid stable, but many are
poorly absorbed. Because they must be
given parenterally, most—including
those with high activity—are used only

in clinical settings. A few, e.g., cepha-
lexin, are suitable for oral use. Cephalo-
sporins are penicillinase-resistant, but
cephalosporinase-forming organisms
do exist. Some derivatives are, however,
also resistant to this !-lactamase.
Cephalosporins are broad-spectrum
antibacterials. Newer derivatives (e.g.,
cefotaxime, cefmenoxin, cefoperazone,
ceftriaxone, ceftazidime, moxalactam)
are also effective against pathogens re-
sistant to various other antibacterials.
Cephalosporins are mostly well tolerat-
ed. All can cause allergic reactions, some
also renal injury, alcohol intolerance,
and bleeding (vitamin K antagonism).
Other inhibitors of cell wall syn-
thesis. Bacitracin and vancomycin
interfere with the transport of pepti-
doglycans through the cytoplasmic
membrane and are active only against
gram-positive bacteria. Bacitracin is a
polypeptide mixture, markedly nephro-
toxic and used only topically. Vancomy-
cin is a glycopeptide and the drug of
choice for the (oral) treatment of bowel
inflammations occurring as a complica-
tion of antibiotic therapy (pseudomem-
branous enterocolitis caused by Clos-
tridium difficile). It is not absorbed.

270 Antibacterial Drugs
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Antibacterial Drugs 271
C. Cephalosporin
A. Disadvantages of penicillin G
B. Derivatives of penicillin G
6-Aminopenicillanic acid
Penicillin G
Penicillinase
Staphylococci
E. coli
Salmonella typhi
Gonococci
Pneumococci
Streptococci
Narrow-action spectrum
Active
Not active
H
+
Cl
-
Resis-
tant
Resistant,
but sensitive
to
cephalosporinase Broad
Cefalexin

Penicillin V
Oxacillin
Amoxicillin
Resis-
tant
Resis-
tant
Resis-
tant
Sensitive
Resistant
Resistant
Narrow
Narrow
Broad
PenicillinaseAcid Spectrum
Concentration needed
to inhibit penicillin G-
sensitive bacteria
Gram-positive Gram-negative
Acid sensitivity Penicillinase
sensitivity
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Inhibitors of Tetrahydrofolate Synthesis
Tetrahydrofolic acid (THF) is a co-en-
zyme in the synthesis of purine bases
and thymidine. These are constituents
of DNA and RNA and required for cell
growth and replication. Lack of THF

leads to inhibition of cell proliferation.
Formation of THF from dihydrofolate
(DHF) is catalyzed by the enzyme dihy-
drofolate reductase. DHF is made from
folic acid, a vitamin that cannot be syn-
thesized in the body, but must be taken
up from exogenous sources. Most bacte-
ria do not have a requirement for folate,
because they are capable of synthesiz-
ing folate, more precisely DHF, from
precursors. Selective interference with
bacterial biosynthesis of THF can be
achieved with sulfonamides and tri-
methoprim.
Sulfonamides structurally resem-
ble p-aminobenzoic acid (PABA), a pre-
cursor in bacterial DHF synthesis. As
false substrates, sulfonamides competi-
tively inhibit utilization of PABA, hence
DHF synthesis. Because most bacteria
cannot take up exogenous folate, they
are depleted of DHF. Sulfonamides thus
possess bacteriostatic activity against a
broad spectrum of pathogens. Sulfon-
amides are produced by chemical syn-
thesis. The basic structure is shown in
(A). Residue R determines the pharma-
cokinetic properties of a given sulfon-
amide. Most sulfonamides are well ab-
sorbed via the enteral route. They are

metabolized to varying degrees and
eliminated through the kidney. Rates of
elimination, hence duration of effect,
may vary widely. Some members are
poorly absorbed from the gut and are
thus suitable for the treatment of bacte-
rial bowel infections. Adverse effects
may include, among others, allergic re-
actions, sometimes with severe skin
damage, displacement of other plasma
protein-bound drugs or bilirubin in neo-
nates (danger of kernicterus, hence con-
traindication for the last weeks of gesta-
tion and in the neonate). Because of the
frequent emergence of resistant bacte-
ria, sulfonamides are now rarely used.
Introduced in 1935, they were the first
broad-spectrum chemotherapeutics.
Trimethoprim inhibits bacterial
DHF reductase, the human enzyme be-
ing significantly less sensitive than the
bacterial one (rarely bone marrow de-
pression). A 2,4-diaminopyrimidine, tri-
methoprim, has bacteriostatic activity
against a broad spectrum of pathogens.
It is used mostly as a component of co-
trimoxazole.
Co-trimoxazole is a combination of
trimethoprim and the sulfonamide sul-
famethoxazole. Since THF synthesis is

inhibited at two successive steps, the
antibacterial effect of co-trimoxazole is
better than that of the individual com-
ponents. Resistant pathogens are infre-
quent; a bactericidal effect may occur.
Adverse effects correspond to those of
the components.
Although initially developed as an
antirheumatic agent (p. 320), sulfasala-
zine (salazosulfapyridine) is used main-
ly in the treatment of inflammatory
bowel disease (ulcerative colitis and
terminal ileitis or Crohn’s disease). Gut
bacteria split this compound into the
sulfonamide sulfapyridine and mesala-
mine (5-aminosalicylic acid). The latter
is probably the anti-inflammatory agent
(inhibition of synthesis of chemotactic
signals for granulocytes, and of H
2
O
2
formation in mucosa), but must be
present on the gut mucosa in high con-
centrations. Coupling to the sulfon-
amide prevents premature absorption
in upper small bowel segments. The
cleaved-off sulfonamide can be ab-
sorbed and may produce typical adverse
effects (see above).

Dapsone (p. 280) has several thera-
peutic uses: besides treatment of lepro-
sy, it is used for prevention/prophylaxis
of malaria, toxoplasmosis, and actino-
mycosis.
272 Antibacterial Drugs
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Antibacterial Drugs 273
A. Inhibitors of tetrahydrofolate synthesis
(Vitamin)
DHF-Reductase
R determines
pharmacokinetics
Duration of effect
Dosing interval
Sulfasalazine
(not absorbable)
Cleavage by
intestinal bacteria
Mesalamine Sulfapyridine
(absorbable)
Bacterium
Human cell
Synthesis of
purines
Thymidine
Sulfonamidesp-Aminobenzoic acid
Combination of
Trimethoprim and

Sulfamethoxazole
Co-trimoxazole =
Dihydro-
folic acid
(DHF)
Tetrahydro- folic acid
Folic acid
Trimethoprim
Sulfisoxazole
6 hours
Sulfamethoxazole
12 hours
Sulfalene
7 days
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Inhibitors of DNA Function
Deoxyribonucleic acid (DNA) serves as a
template for the synthesis of nucleic ac-
ids. Ribonucleic acid (RNA) executes
protein synthesis and thus permits cell
growth. Synthesis of new DNA is a pre-
requisite for cell division. Substances
that inhibit reading of genetic informa-
tion at the DNA template damage the
regulatory center of cell metabolism.
The substances listed below are useful
as antibacterial drugs because they do
not affect human cells.
Gyrase inhibitors. The enzyme gy-

rase (topoisomerase II) permits the or-
derly accommodation of a ~1000 µm-
long bacterial chromosome in a bacteri-
al cell of ~1 µm. Within the chromoso-
mal strand, double-stranded DNA has a
double helical configuration. The for-
mer, in turn, is arranged in loops that
are shortened by supercoiling. The gy-
rase catalyzes this operation, as illus-
trated, by opening, underwinding, and
closing the DNA double strand such that
the full loop need not be rotated.
Derivatives of 4-quinolone-3-car-
boxylic acid (green portion of ofloxacin
formula) are inhibitors of bacterial gy-
rases. They appear to prevent specifical-
ly the resealing of opened strands and
thereby act bactericidally. These agents
are absorbed after oral ingestion. The
older drug, nalidixic acid, affects exclu-
sively gram-negative bacteria and at-
tains effective concentrations only in
urine; it is used as a urinary tract anti-
septic. Norfloxacin has a broader spec-
trum. Ofloxacin, ciprofloxacin, and
enoxacin, and others, also yield system-
ically effective concentrations and are
used for infections of internal organs.
Besides gastrointestinal problems
and allergy, adverse effects particularly

involve the CNS (confusion, hallucina-
tions, seizures). Since they can damage
epiphyseal chondrocytes and joint car-
tilages in laboratory animals, gyrase in-
hibitors should not be used during preg-
nancy, lactation, and periods of growth.
Azomycin (nitroimidazole) deriv-
atives, such as metronidazole, damage
DNA by complex formation or strand
breakage. This occurs in obligate an-
aerobes, i.e., bacteria growing under O
2
exclusion. Under these conditions, con-
version to reactive metabolites that at-
tack DNA takes place (e.g., the hydroxyl-
amine shown). The effect is bactericidal.
A similar mechanism is involved in the
antiprotozoal action on Trichomonas va-
ginalis (causative agent of vaginitis and
urethritis) and Entamoeba histolytica
(causative agent of large bowel inflam-
mation, amebic dysentery, and hepatic
abscesses). Metronidazole is well ab-
sorbed via the enteral route; it is also
given i.v. or topically (vaginal insert).
Because metronidazole is considered
potentially mutagenic, carcinogenic,
and teratogenic in the human, it should
not be used longer than 10 d, if possible,
and be avoided during pregnancy and

lactation. Timidazole may be considered
equivalent to metronidazole.
Rifampin inhibits the bacterial en-
zyme that catalyzes DNA template-di-
rected RNA transcription, i.e., DNA-de-
pendent RNA polymerase. Rifampin acts
bactericidally against mycobacteria (M.
tuberculosis, M. leprae), as well as many
gram-positive and gram-negative bac-
teria. It is well absorbed after oral inges-
tion. Because resistance may develop
with frequent usage, it is restricted to
the treatment of tuberculosis and lepro-
sy (p. 280).
Rifampin is contraindicated in the
first trimester of gestation and during
lactation.
Rifabutin resembles rifampin but
may be effective in infections resistant
to the latter.
274 Antibacterial Drugs
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