Can Bacteria Produce Blockbuster Antibacterial: The Penicillin?
Microbes produce a large number of bioactive molecules. Antibiotics are among the most exploited secondary metabolites. Their consistent and invariably indiscriminate usage by human beings to get rid of plant and animal pathogens has resulted in the emergence of multiple drug resistant microbes. At this juncture, the questions being raised are: (i) Shall we endeavour for novel antibiotics, (ii) Search novel antibiotic producers, (iii) Transform presently “non”-producers to producers by genetically modifying the antibiotic production machinery?
The important antibiotics
β-lactams account for more than 60% of the antibiotics used around the world but there are a few organisms which have the ability to produce them in an efficient manner. Generally, filamentous fungi Penicillium chrysogenum is used for producing Penicilllin G (β-lactam). Bacteria and fungi share high homology in the genes involved in the β-lactam biosynthetic pathway. However, this information has not proved effective in improving β-lactam production efficiency.
Penicillin synthesis proceeds by the formation of tripeptide (ACV) composed of: L-α-aminoadipyl, L-cysteinyl and D-valine, which is mediated by the enzyme ACV synthetase, which in turn gets cyclised to isopenicillin N, with the aid of isopenicillin N synthase (IPNS). The exchange between the α-aminoadipic lateral chain with phenylacetyl-CoA lead to the production of penicillin G. The genes for the synthesis of this antibiotics:pcbAB encoding for ACV synthetase and pcbC encoding for ACV cyclase, show similarity between fungi (Penicillium notatum, P. chrysogenum, and Aspergillus nidulans) and bacteria (Bacillus peptidase genes).
The antibacterial- Penicillin
Penicillin inhibits the biosynthesis of the peptidoglycan layer i.e. the bacterial cell wall. During its biosynthesis, the final step of transpeptidation is carried out by transpeptidases. β-lactam antibiotics - the analogues of D-alanyl-D-alanine, which are the major amino acid residues of the nascent peptidoglycan layer, which is composed of: (i) N-acetyl glucosamine, and (ii) N-acetyl muramic acid peptide subunits. The binding of β-lactam antibiotics inhibits binding proteins (PBP’s), which in turn inhibits the cross-linking of the peptidoglycan layer. The net result is the disruption of cell wall synthesis.
Can bacteria produce penicillin?
We all know that production of penicillin will be counterproductive for the bacteria.
But, Can bacteria produce this antibiotic?
Comparative genomics approach revealed that Burkholderia fungorum and Mesorhizobium loti are two bacterial species, which have genes involved in the biosynthesis of penicillin and cephalosporin. There are a few other bacteria, which lack only one gene responsible for ACV synthetase: Rhodopseudomonas palustris and Magnetospirillum magnetotacticum. Can these bacteria produce penicillin? In principle, it should be possible to use these bacteria by genetically modifying them, say by introducing the missing gene(s).
Why bacteria cannot produce penicillin?
For penicillin production, the organisms needs a machinery composed of: genes for β-lactam biosynthesis, production of α-aminoadipic acid, antibiotic resistance, and efflux of the final product. M. loti and B. fungorum possess most of potential genes, except for ACV synthase and cmcT, respectively. As a consequence, these bacteria have never been identified as β-lactam producers. This hypothesis finds support from strains of Penicillium crustosum and P. verrucosum, which lack penicillin gene clusters and are among the non-producers of β-lactams.
Genomics and bioinformatics can be exploited as tools to search for novel and potential candidates, which can be transformed from “non”-producers to producers.
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About Author / Additional Info:
Researcher at Microbial Biotechnology and Genomics at CSIR-IGIB, Delhi.