Chemistry Reference
In-Depth Information
applied sciences, unraveling novel enzymatic mechanisms and providing tools
for changing chemical structures of some antibiotics to improve their properties.
Because most antibiotics are natural products, their synthesis by living organ-
isms relies on enzymes, proteins with specific catalytic activities. Thus, biosyn-
thesis of antibiotics can generally be described as
enzyme-catalyzed synthesis
of compounds with antibiotic activity in living organisms
. Several enzymes with
different catalytic activities are usually involved in antibiotic biosynthesis, act-
ing in a sequential manner in the synthesis of the antibiotic molecule and form
a biosynthetic pathway. Our current understanding of antibiotic biosynthesis is
mostly based on the studies of biosynthetic pathways in bacteria and fungi, which
are the most prominent antibiotic producers among living organisms. Such stud-
ies have ensured considerable progress in understanding of genetics, enzymology,
and chemistry of antibiotic biosynthesis. Several hundred antibiotic biosynthetic
pathways have been elucidated, unraveling many new and unusual enzymatic
mechanisms. Recent advances in the genome sequencing of antibiotic-producing
organisms and analytical chemistry, along with the development of bioinfor-
matics and chemoinformatics tools, proved to be very useful for elucidation of
new biosynthetic pathways. In this chapter, general mechanisms behind antibiotic
biosynthesis in bacteria and fungi are reviewed.
11.1 BIOLOGY OF ANTIBIOTIC BIOSYNTHESIS
The bacteria and fungi are especially profound in synthesizing chemically
diverse antibiotics, whereas the plants and animals mostly produce ribosomally
synthesized peptides and terpenes with antibiotic activity. Among the bacteria,
species that belong to the order
Actinomycetales
produce over 60% of all
known compounds with antibiotic activity. Some antibiotics of medical and
agricultural importance, along with the information on their chemical class,
biological activity, and producing organisms are presented in Table 11.1.
Antibiotics are synthesized as secondary metabolites, which are not required
for growth and maintenance of the producing organism as do the primary
metabolites (amino acids, lipids, sugars, etc.). The debate on biological function
of antibiotics in terms of their significance for the producing organisms is still
ongoing. One obvious function of antibiotics would be inhibition of growth of
competing organisms to ensure access to nutritional sources in the surrounding
environment. However, in their natural environment, antibiotic-producing
organisms may not synthesize antibiotics in significant amounts, which suggest
an alternative biological role(s). Some antibiotics have been shown to modulate
gene expression in bacteria in subinhibitory concentrations, which implies
that antibiotics may play a role of signaling molecules providing means for
communication between different species (2). Whatever the true biological
function(s) of antibiotics, it must be important for the producing organism,
considering the complexity of their biosynthetic pathways and metabolic burden
imposed by the process of biosynthesis. As exemplified below, many enzymes
