Properties and identification of antibiotic drug targets

Tala M Bakheet,Andrew J Doig

doi:10.1186/1471-2105-11-195

Abstract

BackgroundWe analysed 48 non-redundant antibiotic target proteins from all bacteria, 22 antibiotic target proteins from E. coli only and 4243 non-drug targets from E. coli to identify differences in their properties and to predict new potential drug targets.ResultsWhen compared to non-targets, bacterial antibiotic targets tend to be long, have high β-sheet and low α-helix contents, are polar, are found in the cytoplasm rather than in membranes, and are usually enzymes, with ligases particularly favoured. Sequence features were used to build a support vector machine model for E. coli proteins, allowing the assignment of any sequence to the drug target or non-target classes, with an accuracy in the training set of 94%. We identified 319 proteins (7%) in the non-target set that have target-like properties, many of which have unknown function. 63 of these proteins have significant and undesirable similarity to a human protein, leaving 256 target like proteins that are not present in humans.ConclusionsWe suggest that antibiotic discovery programs would be more likely to succeed if new targets are chosen from this set of target like proteins or their homologues. In particular, 64 are essential genes where the cell is not able to recover from a random insertion disruption.

Highlights

We analysed 48 non-redundant antibiotic target proteins from all bacteria, 22 antibiotic target proteins from E. coli only and 4243 non-drug targets from E. coli to identify differences in their properties and to predict new potential drug targets
The percentage of target helices is 32% compared to 42% for non-targets with significant p-values
After classifying the entire E. coli proteome to identify novel targetlike proteins and pruning it to remove those that are similar to a human protein, we find 256 proteins that may be potential antibiotic targets, especially those 64 proteins highly similar to essential genes

Summary

Introduction

We analysed 48 non-redundant antibiotic target proteins from all bacteria, 22 antibiotic target proteins from E. coli only and 4243 non-drug targets from E. coli to identify differences in their properties and to predict new potential drug targets. Infectious and parasitic diseases caused by pathogenic microorganisms, including bacteria, viruses and fungi, are major threats to human health. Diseases commonly result from exposure to gram positive bacteria, such as Staphylococcus aureus, Streptococcus pneumoniae and group A Streptococcus, and gram negative bacteria, such as E. coli and Helicobacter pylori. Antibacterial drugs are the major weapons to kill bacteria or suppress their activity. Due to the inevitable evolution of antibiotic resistance, the development of novel antibiotics is essential. Antibiotics work either by stopping bacterial growth or by killing the bacteria, without harming the human host. The following are the most common modes-of-action of antibiotics:

Methods

Results

Discussion

Conclusion