New Findings on Bacterial Cell Wall Architecture Herald Possible Return of Penicillin

By tracing the molecular pathway that enables some bacteria to develop resistance to antibiotics, bacteriologists have paved the way for development of drugs to prevent resistance and to reestablish the efficacy of the penicillin-like drugs (beta-lactams).

Worldwide, Streptococcus pneumoniae causes about five million fatal pneumonia infections a year in children. Once the drug of choice to treat pneumonia, penicillin has now largely become ineffective due to development of resistant strains of the pathogen.
Investigators at the University of Warwick (UK) worked with two strains of S. pneumoniae: the penicillin resistant 159 strain and the penicillin susceptible P16 strain. They focused on the activity of the bacterial enzyme MurM, an aminoacyl ligase that adds L-serine or L-alanine as the first amino acid of a dipeptide branch to the stem peptide lysine of the pneumococcal peptidoglycan. The peptidoglycan is a molecular mesh that protects the outside of the bacterium. Penicillin and similar drugs kill bacteria by interfering in the synthesis of the peptidoglycan.

Results published in the March 2008 issue of the Journal of Biological Chemistry revealed that MurM159 attached an alanine group to the peptidoglycan while MurMPn16 activity supported attachment of a serine residue. The difference in structure determined by insertion of alanine or serine was sufficient to render the organism susceptible or resistant to penicillin.

The authors concluded that, "It is anticipated that definition of the minimal structural features of MurM substrates will allow development of novel resistance inhibitors that will restore the efficacy of â-lactams for treatment of pneumococcal infection.”
To help expedite discovery of drugs for this purpose the University of Warwick has established a new network of academics from the fields of chemistry, biology, and medicine, as well as pharmaceutical companies to share and exploit this new treasure trove of potential drug targets.


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