Special Issue "Non-Essential Targets in the Development of Antibiotics and Enhancers of Antimicrobial Therapy"
Deadline for manuscript submissions: closed (31 December 2019).
Interests: PLP-dependent enzymes; cysteine biosynthesis; protein–protein interaction; conditionally essential targets in pathogens; hemophores
Interests: drug discovery; medicinal chemistry; antibacterials; antituberculars
Recent years have seen the increasing incidence of antimicrobial resistance in widespread pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii and the Enterobacteriaceae, with the development of multidrug resistant and extensively drug resistant phenotypes. These bacteria, grouped under the acronym ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), represent the leading cause of nosocomial infections worldwide. Currently, resistance is affecting all antibiotic classes, including the most recently marketed ones such as penems, quinolones and oxazolidindiones. Indeed, the acquistion of resistance is a natural trait of bacteria and it is part of their ability to adapt and evolve in challenging environments.
To tackle antibacterial resistance, either slight chemical modifications of a given molecule, keeping its pharmacophore intact, and/or whole-cell biological screening of compound libraries have been usually carried out. These approaches have in general prevailed over a target-based drug design due to the low rate of success of the latter procedure. For instance, the penetration of molecules through the cell wall, especially in Gram-negative bacteria, represents the most common pitfall that has halted delevopment of otherwise very potent in vitro inhibitors. Nonetheless, “non-essential targets“ have caught the attention of researchers, since they potentially represent a source of unexploited mechanisms that, in principle, tackle bacterial virulence and fitness without directly affecting cell viability, thereby decreasing the selection pressure for resistance to arise. Non-essential targets are, by definition, targets that are dispensable for bacterial growth in vitro and in rich medium, but which may be conditionally important for e.g., invasion or persistance in the host. Targeting proteins and enzymes that are non-essential should, in principle, disarm the pathogen and enable a sustained immune response to clear the infection. However, the conditional essentiality of these targets makes their identification difficult, and to gain adequate insight often requires a multidisciplinary approach, exploiting a combination of biochemistry, molecular biology, microbiology and medicinal chemistry.
Improving our knowledge of well-characterised, virulence-associated targets and finding new conditionally-essential targets in metabolic pathways will lead to a better understanding of the interplay between host and pathogen and will facilitate the discovery of new molecules for the enhancement of antibiotic therapy. In this Special Issue, we aim to assemble some of the more recent insights into non-essential target identification, validation and inhibition.
Dr. Barbara Campanini
Dr. Marco Pieroni
Manuscript Submission Information
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- Antibiotic resistance
- Non-essential targets
- Conditionally essential targets
- Antibiotic adjuvant therapies
- Target-based drug discovery
- Virulence factors
- Combination therapy
- Host-directed therapy