ReviewGene-to-screenIdentifying targets for antibiotic development using omics technologies
Introduction
The use of antibiotics for the treatment and prevention of infections plays a crucial part in modern medicine. Unfortunately, the efficacy of many antibiotic classes in the treatment of different types of bacterial infections has been reduced by the emergence of antibiotic-resistant strains from multiple bacterial species. This alarming trend raises the possibility of what some have termed a ‘post-antibiotic era’ in which certain bacterial infections are no longer treatable with antibiotics [1]. Reports describing pan-resistant infections with strains that demonstrate resistance to all clinically available antibiotics indicate that this possibility could already be a reality in isolated cases 2, 3. The global impact of the dissemination of antibiotic resistance has been underscored recently in multiple studies. In 2014, the World Health Organization reported high rates of antibiotic resistance in all regions of the world [4], and a point-prevalence study carried out by the European Centre for Disease Prevention and Control between 2011 and 2012 that included data from over 900 hospitals in 30 countries showed high resistance rates in healthcare-associated infections [5]. The present and future health burden resulting from antibiotic resistance is significant, as suggested by a recent study commissioned by UK Prime Minister David Cameron in which it was estimated that antimicrobial resistance in selected bacterial, viral and parasitic infections would claim 10 million lives per year by 2050, compared with an estimated 700 000 annual deaths in 2014 [6]. The economic impact is also of importance because the same report projected that the global loss in gross domestic product (GDP) between 2014 and 2050 as a result of antimicrobial resistance would be ∼US$100 trillion [6]. Although these estimates are projections based on currently available data, which in some cases are limited, they are clearly a cause for concern.
In this context, there is a need to develop novel antibiotics with activity against bacterial species that have acquired resistance to multiple antibiotic classes. Traditionally, antibiotic discovery has relied heavily upon identifying natural products with antimicrobial activity and the screening of large collections of compounds. These approaches led to the identification of numerous novel classes of antibiotics for over 30 years starting in the 1940s; however, very few new antibiotics have been introduced onto the market for clinical use over the past two decades [7]. Recently, the development and application of genomic, transcriptomic and proteomic technologies has made it possible to identify and quantify nucleic acids and peptides from complex biological samples. The use of these technologies in the characterization of multiple bacterial species has yielded vast amounts of data regarding different aspects of bacterial physiology. The information obtained from these studies holds great potential for identifying high value bacterial components that can serve as targets for the directed development of antibiotics with novel mechanisms of action. In this review, we discuss how advances in genomic, transcriptomic and proteomic technologies can continue to be used for identifying bacterial targets for antibiotic development and provide salient examples from the recent literature in which these approaches have already yielded valuable information regarding candidate target identification in bacterial species that are associated with antibiotic resistance. Finally, we discuss the future potential of these technologies as well as their limitations in the context of antibiotic development (Table 1).
Section snippets
Comparative genomics and whole genome mutagenesis approaches
Advances in next-generation sequencing technology and bioinformatic applications that facilitate the analysis of large datasets together with the continuing decrease in cost associated with sequencing bacterial genomes have led to an explosion in the number of sequenced bacterial genomes. The availability of tens to thousands of sequenced genomes for some bacterial species can be used in a variety of ways to facilitate antibiotic target identification. Genome sequences obtained from multiple
Using transcriptomic techniques for target identification
Knowledge regarding bacterial gene expression under different environmental conditions can provide important information about the physiological state of the bacterial cell. Techniques that permit the quantification of RNA levels corresponding to a single or a few transcripts include northern blotting and real-time PCR, and have been used widely to characterize bacterial gene expression. With the introduction of microarray technology in the 1990s it became possible to characterize cellular
Target identification using proteomic techniques
Many currently used antibiotics inhibit the function of bacterial proteins to achieve antibacterial activity. In this context, the characterization of bacterial proteomes could provide important information that can be used for candidate target identification. Similar to transcriptomic techniques, comparative proteomics can be used to identify gene products that are expressed under defined environmental conditions. Comparative proteomic approaches have generally employed gel-based and gel-free
Emerging technologies for antibiotic target identification
Studies employing genomic, transcriptomic and proteomic techniques have demonstrated that the characterization of bacterial components at the cellular level can yield vast quantities of information regarding factors that participate in different bacterial processes. Technologies that integrate these methods, such as proteogenomics, or that provide detailed information regarding the state of nucleic acids and proteins, such as kinomics, hold potential for yielding highly detailed information
Using identified targets for antibiotic development
The methods described above can be used to identify bacterial components with characteristics that make them attractive targets for the development of novel antibiotics. Characteristics that can make a potential target attractive include a high level of conservation within a bacterial species and across different species, essentiality for bacterial growth or survival under relevant conditions (e.g. infection, biofilm formation, etc.), lack of homologs in human cells and accessibility for
Concluding remarks
The dwindling antibiotic pipeline together with the global dissemination of antibiotic-resistant strains from multiple bacterial species requires the development of new antibiotics. Discovery programs based on natural compounds and high-throughput screening have yielded few promising compounds within the past two decades. At the same time, genomic, transcriptomic and proteomic technologies that permit the characterization of the cellular repertoire of nucleic acids and proteins have produced
Acknowledgments
The authors thank Pilar Pérez Romero for critical reading of the manuscript. This work was funded by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III – co-financed by Europe's Development Regional Fund ‘a way to achieve Europe’ ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008/0000). M.J.M. is supported by the Subprograma Miguel Servet from the Ministerio de Economía y Competitividad of Spain (CP11/00314). M.R.P. is supported by the
References (42)
- et al.
Pandrug-resistant Gram-negative bacteria: the dawn of the post-antibiotic era?
Int. J. Antimicrob. Agents
(2007) Global transcriptional response of Acinetobacter baumannii to a subinhibitory concentration of tigecycline
Int. J. Antimicrob. Agents
(2014)Bactericidal effect of sulbactam against Acinetobacter baumannii ATCC 19606 studied by 2D-DIGE and mass spectrometry
Int. J. Antimicrob. Agents
(2014)A systematic quantitative proteomic examination of multidrug resistance in Acinetobacter baumannii
J. Proteomics
(2013)Exometabolome analysis identifies pyruvate dehydrogenase as a target for the antibiotic triphenylbismuthdichloride in multiresistant bacterial pathogens
J. Biol. Chem.
(2012)Evaluation of the antimicrobial mode of berberine by LC/ESI–MS combined with principal component analysis
J. Pharm. Biomed. Anal.
(2007)Comprehensive methodology for Staphylococcus aureus lipidomics by liquid chromatography and quadrupole time-of-flight mass spectrometry
J. Chromatogr. A
(2014)A new study of the bacterial lipidome: HPTLC-MALDI-TOF imaging enlightening the presence of phosphatidylcholine in airborne Pseudomonas fluorescens MFAF76a
Res. Microbiol.
(2015)Successful treatment of septic shock due to pan-resistant Acinetobacter baumannii using combined antimicrobial therapy including tigecycline
Eur. J. Clin. Microbiol. Infect. Dis.
(2006)Nosocomial outbreak of infection with pan-drug-resistant Acinetobacter baumannii in a tertiary care university hospital
Infect. Control Hosp. Epidemiol.
(2009)
Antibiotic resistance: global report on, surveillance
Point Prevalance Survey of Healthcare-associated Infections and Antimicrobial use in European Acute Care Hospitals
The drug push
Science
Defining the estimated core genome of bacterial populations using a Bayesian decision model
PLoS Comput. Biol.
What it takes to be a Pseudomonas aeruginosa? The core genome of the opportunistic pathogen updated
PLoS One
Investigating the link between imipenem resistance and biofilm formation by Pseudomonas aeruginosa
Microb. Ecol.
Genetic determinants of intrinsic colistin tolerance in Acinetobacter baumannii
Infect. Immun.
A genetic resource for rapid and comprehensive phenotype screening of nonessential Staphylococcus aureus genes
MBio
Transposon insertion sequencing: a new tool for systems-level analysis of microorganisms
Nat. Rev. Microbiol.
Genes contributing to Staphylococcus aureus fitness in abscess- and infection-related ecologies
MBio
Cited by (0)
- 1
These authors contributed equally to this work.