Small Steps to New Drugs for Bugs

Abstract

Governments, academics and industry are beginning to listen to the medical communities call for new anti-bacterials. This special issue brings together diverse review articles on topics from economics and pricing to new discovery methods.

Thiol activated prodrugs of sulfur dioxide (SO2) as MRSA inhibitors

“…Although efforts to develop new drug candidates with novel mechanisms of action have intensified, the growing number of multidrug resistant MRSA infections has further accentuated the problem of antibiotic resistance necessitating new strategies to target such drug-resistant bacteria. [1][2][3][4][5][6][7] Sulfur dioxide (SO 2 ) is a gaseous environmental pollutant produced during volcanic eruptions and fossil fuel combustion. 8 At elevated levels, SO 2 is toxic to cells and among the various modes for cellular stress induction by SO 2 , perturbation of redox homeostasis through generation of oxidative species has been reported.…”

Subcellular Chemical Imaging of Antibiotics in Single Bacteria Using C60-Secondary Ion Mass Spectrometry

“…3−5 These problems are exacerbated by the slow rate of discovery and approval of new effective treatments for antibiotic-resistant Gram-negative bacterial infections. 4,6,7 Gram-negative pathogens are challenging targets for drug discovery largely because promising antibiotics fail to accumulate to effective levels within the intracellular compartment(s) of the cell. 8−10 The accumulation problem arises initially from an outer membrane permeability barrier that restricts influx of large and/or hydrophobic molecules.…”

“…Gram-negative bacterial pathogens are increasingly resistant to the approved treatments, , which has led to the use of drugs of last resort (e.g., colistin) that are less safe and are also losing efficacy. − These problems are exacerbated by the slow rate of discovery and approval of new effective treatments for antibiotic-resistant Gram-negative bacterial infections. ,, Gram-negative pathogens are challenging targets for drug discovery largely because promising antibiotics fail to accumulate to effective levels within the intracellular compartment(s) of the cell. − The accumulation problem arises initially from an outer membrane permeability barrier that restricts influx of large and/or hydrophobic molecules. Many of the smaller, polar compounds that can penetrate this outer membrane barrier through aqueous porins to the periplasm can then be ejected from the cells by one or more tripartite resistance-nodulation-cell division (RND) efflux pumps .…”

Assessing Antibiotic Permeability of Gram-Negative Bacteria via Nanofluidics

“…The spread of bacteria pathogens poses a significant threat to communities around the world. − Antibiotic-resistant bacteria can limit modern therapies, such as joint replacement, transplant, and chemotherapy. The development of efficient, potent antibiotics is challenging − because effective compounds not only need to demonstrate high biochemical inhibitory activity against their molecular targets, but some classes also need to be able to penetrate the cell envelope to reach the intracellular compartments where many of the drug targets are located . This is particularly difficult in Gram-negative bacteria because the cell envelope consists of an outer and inner membrane with different chemical and biophysical properties. , Small molecules within a permissive chemical space traverse the outer membrane of Gram-negative bacteria through aqueous porins then passively diffuse or are actively transported through the inner membrane, competing against active efflux by numerous transmembrane pumps .…”