Bacterial Response to Starvation Breeds Resilience
McGill University ♦ Published in Science, November 18, 2011
Biofilms are one of the primary mechanisms by which bacteria evade the toxic effect of antibiotics. Using a process known as quorum sensing bacteria can communicate amongst one another to accumulate in unison on a surface, living, synthetic, or natural. The benefits provided to the bacteria in film-formation are two-fold: firstly, the density of the bacteria reduces bacterial exposure to antibiotics, and secondly, a protective layer eventually encases the film as it exudes heavy polymeric substances.
However, there is a consequence to biofilm formation — nutrient deprivation and starvation. One would think this to be a disadvantage, but it actually further increases bacterial resistance to antibiotics. One hypothesis to explain this phenomenon is that starvation induces growth arrest and that this reduces the activity of factors that antibiotics require to kill bacteria. New findings from McGill indicate that there is more to the explanation than the passive resistance created through growth arrest. Researchers have discovered an active response to starvation, the starvation-signaling stringent response (SR), which increases tolerance to antibiotics. During times of starvation the SR mechanism is activated leading to a reduction in the burden of oxidants inside bacterial cells. A key finding in this study was that bacteria could be sensitized to antibiotics, by several orders of magnitude, by interfering with the SF mechanism.
Cystic fibrosis (CF) is a good example of a disease indication where biofilms contribute to morbidity. Aggressive Pseudomonas aeruginosa infections occur in the lungs and airways of CF patients. These infections can be treated during the early stages of the disease, however resistant biofilms lead to bacterial adaptation and chronic infection, which ultimately causes fatal complications. Future therapies for biofilms will likely involve a multi-faceted approach that target the many pathways and signaling mechanisms that lead to their formation.
Repression of Mitochondrial Translation: New Therapeutic Approach for AML
Ontario Cancer Institute ♦ Published in Cancer Cell, November 15, 2011
A chemical screen has identified the small molecule tigecycline as a potent suppressor of acute myeloid leukemia (AML). The screen involved 312 drugs that had already been approved by the FDA, both on-patent and off-patent, and focused on those that were well characterized antimicrobials or metabolic regulators. Tigecycline exhibited cytotoxic effects on two human AML cell lines, while having little effect on their normal hematopoietic counterparts. The molecule also had antileukemic activity in a mouse model of human leukemia. A genome-wide screen in yeast was carried out to elucidate tigecycline’s mechanism of action. The small molecule was found to inhibit a transcription factor. The interesting finding was that inhibition was not cytoplasmic, but instead mitochondrial. Tigecyline likely interacts with the EF-Tu transcription factor in the mitochondria, as researchers found they could mimic tigecycline’s effects by downregulating expression of EF-Tu using shRNAs.