Protein-protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics.

Laura Carro

doi:10.3762/bjoc.14.267

Abstract

Antibiotics are potent pharmacological weapons against bacterial infections; however, the growing antibiotic resistance of microorganisms is compromising the efficacy of the currently available pharmacotherapies. Even though antimicrobial resistance is not a new problem, antibiotic development has failed to match the growth of resistant pathogens and hence, it is highly critical to discover new anti-infective drugs with novel mechanisms of action which will help reducing the burden of multidrug-resistant microorganisms. Protein–protein interactions (PPIs) are involved in a myriad of vital cellular processes and have become an attractive target to treat diseases. Therefore, targeting PPI networks in bacteria may offer a new and unconventional point of intervention to develop novel anti-infective drugs which can combat the ever-increasing rate of multidrug-resistant bacteria. This review describes the progress achieved towards the discovery of molecules that disrupt PPI systems in bacteria for which inhibitors have been identified and whose targets could represent an alternative lead discovery strategy to obtain new anti-infective molecules.

Highlights

Bacterial infections are one of the most frequent diseases in humans and livestock, and one of the top ten causes of death according to the World Health Organization [1]
The X-ray analysis revealed that ROCS very accurately predicted the binding mode and validated its use as an alternative approach to identify new promising leads as inhibitors of this protein–protein interaction. These compounds were not found to be therapeutically relevant inhibitors of the Z interaction protein A (ZipA)/Filamenting temperature-sensitive protein Z (FtsZ) protein–protein interaction, considering the challenges involved in targeting Protein–protein interactions (PPIs), it is significant that the authors demonstrated by NMR that compounds from this library bind to ZipA at the FtsZ binding site and that small molecule disruptors of the ZipA/FtsZ interaction could inhibit cell division in both Gram-positive and Gram-negative microorganisms, findings that could be of value in the development of optimized antagonists for potential use as antibacterials
Due to the fact that new resistant microorganisms continue to emerge, combating these infections has become a global challenge for which the discovery and development of new antibacterial drugs is of critical importance

Summary

Introduction

Bacterial infections are one of the most frequent diseases in humans and livestock, and one of the top ten causes of death according to the World Health Organization [1]. The serendipitous discovery of penicillin and its introduction into the clinic in the first half of the 20th century gave rise to the “Golden Age” of antibiotics discovery and have unquestionably represented one of the most important achievements in medicine Since their use is intrinsically linked to the appearance of resistance, threatening antibiotic-resistant bacteria levels are being observed, compromising the efficacy of most available antibiotics to cure infectious diseases [2,3,4]. The WHO recently published a list of global priority antibiotic-resistant bacteria to help prioritizing the research and development of new and effective antibiotic treatments [8]. In this list the pathogens were ranked in three priority levels according to the species and type of resistance: 1. Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant, 3rd generation cephalosporin-resistant

Priority 2 – High:

Findings

Conclusion