Active and passive resistance mechanisms of Bacillus subtilis against cell envelope targeting antibiotics
Modern medicine relies on the use of antibiotics to treat infectious diseases caused by bacteria and save millions of lives. But bacteria acquire resistances with an alarming rate, rendering many antibiotics ineffective. As such, wise use of antibiotics to prevent the emergence of resistance is of u...
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|Summary:||Modern medicine relies on the use of antibiotics to treat infectious diseases caused by bacteria and save millions of lives. But bacteria acquire resistances with an alarming rate, rendering many antibiotics ineffective. As such, wise use of antibiotics to prevent the emergence of resistance is of utmost importance.
To utilize antibiotics more efficiently environmental conditions and the general structure of biochemical pathways should also be taken in account as they can have significant impact on susceptibility. In this work, the susceptibility of the gram-positive bacterium Bacillus subtilis against cell envelope targeting antibiotics was analyzed. As a member of the Firmicutes phylum and due to the strong conservation of cell wall synthesis the findings gained here in B. subtilis provide valuable insight into the resistance of dangerous pathogenes of the same phylum like Staphylococcus aureus and Clostridium tetani.
First, the natural cell envelope stress response towards the novel antibiotic laspartomycin C was investigated. Interestingly, while the very similar antibiotic friulimicin B only induces the sigma M module, laspartomycin C additionally activates the Lia- and the two Bce-like resistance modules tested here. We hypothesize that these differences arise from small but impactful differences in the antibiotics structure that allow a multimerization of UP-bound friulimicin B on the one hand and cause a higher disturbance of the membrane by laspartomycin C on the other hand. The resistance conferred by these modules was further examined via deletion strains. None of the modules tested here provided any protection against either of the two antibiotics.
For a potential use of these antibiotics as clinical drugs the lack of conferred resistance is promising. However, the induction of the natural resistance modules by laspartomycin C might indicate their impending evolution to provide full resistance and should be kept in mind in further studies.
Slow growth is associated with resistance against environmental stresses and antibiotics. In many cases this higher resistance is caused by a slower metabolism and therefore a slow damaging effect by the environmental stress or antibiotic. Besides the overall metabolic rate, the metabolism of bacteria is also heavily regulated in dependence of growth rate. For instance, fast growing bacteria are significantly bigger in cell size and are therefore expected to require more cell wall material. As such, the emergence of bottlenecks was expected with the upregulation of its synthesis, which should ultimately lead to changes in susceptibility of cell wall targeting antibiotics dependent on growth rate.
Here, inhibitory concentrations of a diverse set of cell envelope targeting antibiotic were determined in a range of different growth rates. Contrary to our expectations, the resistance towards most tested cell envelope targeting antibiotics was independent of growth rate. Only the cell envelop targeting antibiotic bacitracin showed a growth rate depended change of the susceptibility with a 40% increase of the inhibitory concentration. Compared to ribosome-targeting antibiotics, which have been shown to increase by up to 500% in activity in the same growth rate range, this increase in resistance seems less substantial. This indicates a tight regulation of the cell wall synthesis machinery, that impedes the emergence of bottlenecks despite changing demands of cell wall material. As such, cell envelope targeting antibiotics are versatile tools in the combat against both slow-growing and chronic, as well as fast-growing and acute infections.|