Penicillin resistance mystery unravelled

Penicillin resistance mystery unravelled

A new study by researchers in the UK, Canada and the US has unravelled the mystery of penicillin resistance in a bacterium that causes fatal pneumonia, signalling the possibility that one day the antibiotic discovered by Alexander Fleming in 1928 could make a comeback. The researchers hope their findings will also help develop designer antibiotics to fight MRSA and other dangerous bacteria.

The study is published in the 7 March issue of the Journal of Biological Chemistry and was led by Dr Adrian Lloyd, of the Department of Biological Sciences at Warwick University, UK, and other colleagues from Warwick, the Université Laval, Ste-Foy in Quebec, and The Rockefeller University in New York.

Streptococcus pneumoniae is responsible for 5 million child deaths every year across the world. It also kills 7 per cent of the 1 million elderly Americans that catch pneumococcal pneumonia every year.

Lloyd and his team have not only discovered exactly how the bacterium becomes immune to penicillin, but they believe the finding reveals how to disrupt the bacterium's resistance so that penicillin can regain its former potency as an antibiotic.

Penicillin weakens bacteria by stopping them building cell walls properly; it blocks their ability to make the protective mesh that surrounds each cell. The mesh is called the Peptidoglycan and is present in several types of bacteria, including Streptococcus pneumoniae and MRSA.

The researchers found that penicillin resistant S. pneumoniae bacteria use a protein, MurM, as an enzyme to help build dipeptide bridges within the peptidoglycan. A high level of dipeptide bridges in the peptidoglycan "mesh" appears to be a pre-requisite for high resistance to penicillin. This has been found from sampling penicillin resistant strains of Streptococcus pneumoniae in patients with pneumococcal infections.

The team at Warwick managed to replicate the action of MurM in the laboratory where they were able to follow the step by step chemistry of peptidoglycan synthesis.

They compared the chemical behaviour of penicillin-resistant and penicillin-susceptible strains of Streptococcus pneumoniae and showed that they used MurM differently. They were able to pinpoint the exact step where the more resistant strain may have made an evolutionary leap and thereby gained competitive advantage.

MurM in the highly penicillin-resistant Streptococcus pneumoniae strain 159 supported more alanylation than serylation, while MurM in the penicillin-susceptible strain Pn16 supported serylation more than alanylation in the synthesis of peptidoglycan.

These findings will allow researchers to target MurM chemistry in Streptococcus pneumoniae in a way that undermines this advantageous step and thus disrupt the bacterium's resistance to penicillin.

Similarly, because MRSA and other bacteria use the same type of peptide bridges to synthesize their peptidoglycan protective mesh, it may be possible to use this knowledge to make penicillin potent against them as well.

Another spinoff is that the tools that Lloyd and colleagues used to trace every step involved in the synthesis of peptidoglycan by Streptococcus pneumoniae can be used to look at similar processes in other dangerous bacteria, thus opening a new avenue for the development of designer antibiotic drugs that disrupt resistance.

As with much breakthrough research, it is not just the new tools that become valuable but the network of relationships and contacts whose collaboration form a reservoir of team skills and talents for future developments. In this case, the new network is called the UK Bacterial Cell Wall Biosynthesis Network or UK-BaCWAN, and comprises academics from chemistry, biology and medicine, as well as biotech companies.

"Characterization of tRNA-dependent Peptide Bond Formation by MurM in the Synthesis of Streptococcus pneumoniae Peptidoglycan."

Adrian J. Lloyd, Andrea M. Gilbey, Anne M. Blewett, Gianfranco De Pascale, Ahmed El Zoeiby, Roger C. Levesque, Anita C. Catherwood, Alexander Tomasz, Timothy D. H. Bugg, David I. Roper, and Christopher G. Dowson.

J. Biol. Chem. Vol. 283, Issue 10, pp 6402-6417, March 7, 2008

DOI :10.1074/jbc.M708105200

Click here for Abstract.

Click here for UK Bacterial Cell Wall Biosynthesis Network (UK- BaCWAN).

Sources: BBC News,.

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Section Issues On Medicine: Disease