The ultimate source of many of these genes is almost certainly the actinomycetes that make the antibiotics and therefore need self‐protective mechanisms to avoid suicide. How do they ensure that they are resistant at the time when intracellular antibiotic concentrations reach potentially lethal levels?
Antibiotics, as typical secondary metabolites, are usually not produced during early vegetative growth of the actinomycetes, but start to be made as growth slows and enters the stationary phase.
In order to act effectively in antibiotic self‐protection,
- the resistance‐conferring proteins,
- antibiotic‐modifying and target‐protecting enzymes,
- or export pumps – must be present in sufficiently high concentrations at this critical moment when the biosynthetic pathway has begun to produce the antibiotic.
- Streptomyces produce various bioactive natural products and possess resistance systems for these metabolites, which are co-regulated with antibiotic biosynthesis genes.
- Microorganisms require one or more self-resistance determinants to produce antibiotics; these encode proteins that inactivate the antibiotic, facilitate its export, or modify the host to render it insensitive to the antibiotic (Cundliffe 1989).
- Multiple resistance mechanisms are often found; in such cases, it is not known whether any one resistance mode is sufficient to ensure survival or antibiotic production.
There is considerable anecdotal evidence that high‐yielding strains of antibiotic‐producing streptomycetes tend to start their growth cycle with only a low or moderate level of resistance, which increases at the time of antibiotic production.
Tahlan et al. describe a mechanism, which they dub ‘feed‐forward’ regulation, by which an antibiotic‐producing streptomycete is primed for resistance by sensing an antibiotically inactive precursor of the active end‐product of the biosynthetic pathway, leading to transcription of the genes for an export mechanism before the intracellular concentration of the antibiotic reaches a toxic level. They propose this as the first characterized example of a general phenomenon to prepare an organism for resistance at the time when it is needed.
The authors coin the name ‘feed‐forward’ for the phenomenon in which an inactive precursor of an antibiotic acts as a signal to prepare the organism for the later build‐up of a toxic level of an exported antibiotic, and they suggest that it could be a common means by which bacteria co‐ordinate the biosynthesis and export of secondary metabolites.