[show abstract][hide abstract] ABSTRACT: Amphiphilic aminoglycoside antibiotics kill bacteria by disruption of their highly negatively charged membrane. In their Communication (DOI:10.1002/anie.201200761), M. Fridman and co-workers report the synthesis of 6''-thioether tobramycin derivatives and show that their aliphatic chain acts as a drill bit that can rupture bacterial cells. These potent compounds evade many of the common bacterial resistance mechanisms, thereby opening a new avenue for the discovery of membrane-targeting antibiotics.
Angewandte Chemie International Edition 05/2012; · 13.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Amphiphilic tobramycin analogues with potent antibacterial activity against tobramycin-resistant bacteria were synthesized. Most analogues were found to be less prone to deactivation by aminoglycoside-modifying enzymes than tobramycin. These compounds target the bacterial membrane rather than the ribosome. The lipophilic residue of these analogues is key to their antibacterial potency and selectivity towards bacterial membranes.
Angewandte Chemie International Edition 04/2012; 51(23):5652-6. · 13.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Signaling photoreceptors mediate diverse organismal adaptations in response to light. As light-gated protein switches, signaling photoreceptors provide the basis for optogenetics, a term that refers to the control of organismal physiology and behavior by light. We establish as novel optogenetic tools the plasmids pDusk and pDawn, which employ blue-light photoreceptors to confer light-repressed or light-induced gene expression in Escherichia coli with up to 460-fold induction upon illumination. Key features of these systems are low background activity, high dynamic range, spatial control on the 20-μm scale, independence from exogenous factors, and ease of use. In optogenetic experiments, pDusk and pDawn can be used to specifically perturb individual nodes of signaling networks and interrogate their role. On the preparative scale, pDawn can induce by light the production of recombinant proteins and thus represents a cost-effective and readily automated alternative to conventional induction systems.
Journal of Molecular Biology 03/2012; 416(4):534-42. · 3.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Bacterial phenotypic variability--the display of multiple distinct phenotypes in a genetically homogenous population of bacteria-emerges as an adaptive response to conflicting challenges. This creates an opportunity for social interactions which are able to dynamically redistribute cell fates within a community and to directly share the benefits of the different fates. While social interactions between cell fates can optimize community behavior, they also make the community vulnerable to exploitation. The aim of this review is to emphasize the social roles of phenotypic variability and introduce it as a communal rather than a single-cell property. Specifically, we present two prevalent perspectives on the forces shaping social interactions between cell fates--engineering optimality and social stability--and review recent works combining engineering, developmental and social evolution analyses in light of this distinction.
Current opinion in genetics & development 12/2011; 21(6):759-67. · 8.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: In microbial "quorum sensing" (QS) communication systems, microbes produce and respond to a signaling molecule, enabling a cooperative response at high cell densities. Many species of bacteria show fast, intraspecific, evolutionary divergence of their QS pathway specificity--signaling molecules activate cognate receptors in the same strain but fail to activate, and sometimes inhibit, those of other strains. Despite many molecular studies, it has remained unclear how a signaling molecule and receptor can coevolve, what maintains diversity, and what drives the evolution of cross-inhibition. Here I use mathematical analysis to show that when QS controls the production of extracellular enzymes--"public goods"--diversification can readily evolve. Coevolution is positively selected by cycles of alternating "cheating" receptor mutations and "cheating immunity" signaling mutations. The maintenance of diversity and the evolution of cross-inhibition between strains are facilitated by facultative cheating between the competing strains. My results suggest a role for complex social strategies in the long-term evolution of QS systems. More generally, my model of QS divergence suggests a form of kin recognition where different kin types coexist in unstructured populations.
Proceedings of the National Academy of Sciences 08/2011; 108(33):13635-40. · 9.74 Impact Factor