oa Editorial [Hot topic: New Approaches to Target Gram-Negative Bacteria (Guest Editor: Yanming Du)]

Multidrug-resistant Gram-negative bacteria, including the strains Escherichia, Klebsiella, Pseudomonas, and Acinetobacter, have become imminent threats to public health and welfare due to the lack of safe and broadly effective drugs in the markets, which is accompanied by the shortage of investigational compounds in clinical trials. These bacterial strains render known antibiotics either less effective or inactive through the reduction of intracellular permeability or increased extrusion, enzymatic inactivation (or degradation), or target modification. Comparatively, Gram-negative bacteria create the need for more advanced solutions to facilitate drug penetration and prevent ejection than Gram-positive pathogens require due to their outer membrane, which is covered with lipopolysaccharides and host for efflux pumps. Several enabling technologies have been developed and broadly applied in the antibiotics discovery area for decades. These include combinatorial chemistry and high throughput screening to facilitate the identification of promising hits and X-ray or NMR techniques, which increase the understanding of the structures of the targets and their interactions with ligands. The pool of genomic information for discovering new targets has also increased over time. Nevertheless, the transformation of potent hits and ligands to drug candidates with good efficacies and safety profiles continues to be a major challenge. To overcome resistance, new targets are continuously sought with the expectation of generating a new class of compounds. Efflux pumps and various types of enzymes have been explored. Compounds with novel structures interacting with known targets are also under investigation due to the lower probability of resistance to such structures. In addition, the modification of known antibiotics has been of interest in the discovery effort. There are ample examples in antibiotics' history indicating that a partial change of a core structure may lead to new antibiotics with different properties and antibacterial spectra, such as penicillin to cephalosporin or carbapenem, and erythromycin to azithromycin. However, history has also taught us that the window for bacteria to accept the structural variations is very narrow. Elegant design, as well as perhaps some good fortune, often essential for success. In this issue of “Current Topics in Medicinal Chemistry,” five papers have been assembled. They reflect the progress in understanding new promising targets and the development of either a new class of compounds or derivatives of known antibiotics to overcome resistance in Gram-negative pathogens. Here are the highlights. Efflux pumps and their inhibitors have attracted great attention, not only because of the success of β-lactamase inhibitors in recovering the efficacy of β-lactam antibiotics, but also because they are obstacles that most antibiotics must overcome. In the first review of this issue, Jean-Marie Pages, Sandrine Alibert-Franco, Abdallah Mahamoud, Jean-Michel Bolla, Anne Davin- Regli, Jacqueline Chevalier, and Eric Garnotel described the recent progress in the characterization of efflux pump structures. These authors presented potential efflux pump targets under a real dynamic environment and insightfully introduced the six strategies currently being pursued to circumvent efflux pumps. Furthermore, they also discussed five types of efflux pump inhibitors, highlighting the advances as well as the challenges associated with each type. The isoprenoid biosynthetic pathway has been extensively explored, and the enzymes involved in this pathway have been investigated as targets for the treatment of many human diseases. However, much less attention has been paid so far to them as potential targets for antibiotics. Andrew J. Wiemer, Chia-Hung Christine Hsiao, and David F. Wiemer covered the necessity of isoprenoid biosynthesis for bacterial growth and presented the differences between Human and Enterbacteria isoprenoid biosynthesis pathways. In the opening to their contribution, they provided an example showing that Enterobacteria carried out isoprenoid biosynthesis on a different pathway from eukaryotes. Inhibition of an enzyme, 1-deoxy-D-xylulose-5-phosphate reductoisomerase, used in this pathway led to the discovery of potent compounds active against Gram-negative bacteria. More pathways associated with quinone synthesis, bacterial electron transport chain and cell wall biosynthesis were discussed in detail, and enzymes were carefully selected as potential targets selective for bacterial species. Inhibitors that were developed for these enzymes have been presented, as well as the knowledge about inhibitor design, including charge and steric considerations.