Antimicrobial Agents in the Treatment of Infectious Disease
(page 5)
(This chapter has 6 pages)
© 2009 Kenneth Todar, PhD
Effects on Nucleic Acids
Some antibiotics and chemotherapeutic agents affect the synthesis of
DNA or RNA, or can bind to DNA or RNA so that their messages cannot be
read. Either case, of course, can block the growth of cells. The
majority of these drugs are unselective, however, and affect animal
cells and bacterial cells alike and therefore have no therapeutic
application. Two nucleic acid synthesis inhibitors which have selective
activity against procaryotes and some medical utility are the quinolones
and rifamycins.
Nalidixic acid is a synthetic chemotherapeutic agent that
has activity
mainly against Gram-negative bacteria. Nalidixic acid belongs to a
group
of compounds called quinolones. Nalidixic acid is a bactericidal agent
that
binds to the DNA gyrase enzyme (topoisomerase) which is essential for
DNA
replication and allows supercoils to be relaxed and reformed. Binding
of
the drug inhibits DNA gyrase activity.
Some quinolones penetrate macrophages and neutrophils better than
most antibiotics and are thus useful in treatment of infections caused
by intracellular parasites. However, the main use of nalidixic acid is
in treatment of lower urinary tract infections (UTI). The compound is
unusual in that it is effective against several types of Gram-negative
bacteria such as E. coli, Enterobacter aerogenes, K. pneumoniae
and Proteus species which are common causes of UTIs. It is not
usually effective against Pseudomonas aeruginosa, and
Gram-positive bacteria may be resistant. Some quinolones have a
broadened spectrum against Gram-positive
bacteria. The fluoroquinolone, Cipro. (ciprofloxacin) was
recently touted as the drug of choice for treatment and prophylaxis of
anthrax, which is caused by a Gram-positive bacillus, Bacillus anthracis.
Ciprofloxacin
(cipro), a fluoroquinolone is a broad-spectrum antimicrobial agent that
is active against both Gram-positive and Gram-negative bacteria. It
functions by inhibiting DNA gyrase, a type II topoisomerase, which is
an enzyme necessary to separate replicated DNA, and thereby inhibits
cell division.
The rifamycins are a comparatively new group of antibiotics,
also the products of Streptomyces species. Rifampicin is
a
semisynthetic derivative of rifamycin that is active against
Gram-positive bacteria (including Mycobacterium tuberculosis)
and some Gram-negative bacteria. Rifampicin acts quite
specifically on the bacterial RNA polymerase and is inactive towards
DNA polymerase or RNA polymerase from animal cells. The antibiotic
binds to the beta subunit of the polymerase and apparently blocks the
entry of the first nucleotide which is necessary to activate the
polymerase, thereby blocking mRNA synthesis. It has been found to have
greater bactericidal effect against M. tuberculosis than other
anti-tuberculosis drugs, and it has largely replaced isoniazid as one
of the front-line drugs used to treat the disease, especially when
isoniazid resistance is indicated. It is effective orally and
penetrates the cerebrospinal fluid so it is useful for treatment of
bacterial meningitis.
Rifampicin
(or rifampin) is a bactericidal antibiotic from the
rifamycin group. It is a semisynthetic compound derived from
Amycolatopsis rifamycinica
(formerly known as Amycolatopsis
mediterranei and
Streptomyces
mediterranei). Rifampicin is
typically used to treat Mycobacterium
infections,
including tuberculosis and leprosy; and also has a role in the
treatment of methicillin-resistant Staphylococcus
aureus
(MRSA) in combination with fusidic acid. It is used in
prophylactic therapy against
Neisseria meningitidis (meningococcal)
infection. It is
also used to treat infection by Listeria
monocytogenes, Neisseria gonorrhoeae, Haemophilus influenzae and
Legionella
pneumophila.
chapter continued
Previous Page
