Question

(c) Briefly explain how erythromycin-producing bacteria (Streptomyces) avoid being killed by the antibiotic, and hence outline a potential problem associated with efforts to obtain novel erythromycin analogues by re-engineering the native gene cluster for erythromycin biosynthesis. (3 points)

Answer 1

Erythromycin belongs to the class of antibiotics known as macrolide. This class antibiotic inhibits protein synthesis by interrupting the process of translation by binding to the larger subunit of the ribosome 50s. The erythromycin producing bacteria take the help of efflux pumps to pump out the erythromycin content diffusing inside the cell. These pumps are not present in the case of the other bacteria which leads them to inhibit the protein synthesis and ultimately death. Thus the mechanism behind the erythromycin bacteria to not affect by the antibiotic is that macrolides such as erythromycin will diffuse inside the cell but will be thrown out of the cell through such efflux pumps which makes the bacteria resistant to that antibiotic. Effective efflux pumps that are useful in the pumping out process are encoded by the mefA and mefF genes which are important for the synthesis of these pumps and working of them on the plasma membrane. These genes can be transferred horizontally to the other bacteria to make them resistant against such macrolide.

In case of the re-engineering of the analog through on the gene level, it causes many problems because the efflux pumps are specifically targeting the erythromycin but even if any analog has been synthesized the bacteria will not be able to recognize as the erythromycin and thus they will not be able to throw that material out of the cell thus it can lead to the apoptosis or the death of the bacteria due to its accumulation. Hence, it is very difficult to re-engineer the analog for the other macrolide. The gene has to be specific for the amino acid sequence as per the erythromycin and some of the changes can be made which will not affect the action of the drug. The binding of the drug is checked and analyzed similarly to the erythromycin but the structure of the drug varies thus it is important to develop in such a way that the pumps can throw it out of the cell without harming the cells.