TY - JOUR AB - We developed a competition-based screening strategy to identify compounds that invert the selective advantage of antibiotic resistance. Using our assay, we screened over 19,000 compounds for the ability to select against the TetA tetracycline-resistance efflux pump in Escherichia coli and identified two hits, β-thujaplicin and disulfiram. Treating a tetracycline-resistant population with β-thujaplicin selects for loss of the resistance gene, enabling an effective second-phase treatment with doxycycline. AU - Stone, Laura AU - Baym, Michael AU - Lieberman, Tami AU - Chait, Remy P AU - Clardy, Jon AU - Kishony, Roy ID - 1290 IS - 11 JF - Nature Chemical Biology TI - Compounds that select against the tetracycline-resistance efflux pump VL - 12 ER - TY - CONF AB - In recent years, several biomolecular systems have been shown to be scale-invariant (SI), i.e. to show the same output dynamics when exposed to geometrically scaled input signals (u → pu, p > 0) after pre-adaptation to accordingly scaled constant inputs. In this article, we show that SI systems-as well as systems invariant with respect to other input transformations-can realize nonlinear differential operators: when excited by inputs obeying functional forms characteristic for a given class of invariant systems, the systems' outputs converge to constant values directly quantifying the speed of the input. AU - Lang, Moritz AU - Sontag, Eduardo ID - 1320 TI - Scale-invariant systems realize nonlinear differential operators VL - 2016-July ER - TY - JOUR AB - Antibiotic-sensitive and -resistant bacteria coexist in natural environments with low, if detectable, antibiotic concentrations. Except possibly around localized antibiotic sources, where resistance can provide a strong advantage, bacterial fitness is dominated by stresses unaffected by resistance to the antibiotic. How do such mixed and heterogeneous conditions influence the selective advantage or disadvantage of antibiotic resistance? Here we find that sub-inhibitory levels of tetracyclines potentiate selection for or against tetracycline resistance around localized sources of almost any toxin or stress. Furthermore, certain stresses generate alternating rings of selection for and against resistance around a localized source of the antibiotic. In these conditions, localized antibiotic sources, even at high strengths, can actually produce a net selection against resistance to the antibiotic. Our results show that interactions between the effects of an antibiotic and other stresses in inhomogeneous environments can generate pervasive, complex patterns of selection both for and against antibiotic resistance. AU - Chait, Remy P AU - Palmer, Adam AU - Yelin, Idan AU - Kishony, Roy ID - 1332 JF - Nature Communications TI - Pervasive selection for and against antibiotic resistance in inhomogeneous multistress environments VL - 7 ER - TY - JOUR AB - A key aspect of bacterial survival is the ability to evolve while migrating across spatially varying environmental challenges. Laboratory experiments, however, often study evolution in well-mixed systems. Here, we introduce an experimental device, the microbial evolution and growth arena (MEGA)-plate, in which bacteria spread and evolved on a large antibiotic landscape (120 × 60 centimeters) that allowed visual observation of mutation and selection in a migrating bacterial front.While resistance increased consistently, multiple coexisting lineages diversified both phenotypically and genotypically. Analyzing mutants at and behind the propagating front,we found that evolution is not always led by the most resistant mutants; highly resistant mutants may be trapped behindmore sensitive lineages.TheMEGA-plate provides a versatile platformfor studying microbial adaption and directly visualizing evolutionary dynamics. AU - Baym, Michael AU - Lieberman, Tami AU - Kelsic, Eric AU - Chait, Remy P AU - Gross, Rotem AU - Yelin, Idan AU - Kishony, Roy ID - 1342 IS - 6304 JF - Science TI - Spatiotemporal microbial evolution on antibiotic landscapes VL - 353 ER - TY - CONF AB - Crossing fitness valleys is one of the major obstacles to function optimization. In this paper we investigate how the structure of the fitness valley, namely its depth d and length ℓ, influence the runtime of different strategies for crossing these valleys. We present a runtime comparison between the (1+1) EA and two non-elitist nature-inspired algorithms, Strong Selection Weak Mutation (SSWM) and the Metropolis algorithm. While the (1+1) EA has to jump across the valley to a point of higher fitness because it does not accept decreasing moves, the non-elitist algorithms may cross the valley by accepting worsening moves. We show that while the runtime of the (1+1) EA algorithm depends critically on the length of the valley, the runtimes of the non-elitist algorithms depend crucially only on the depth of the valley. In particular, the expected runtime of both SSWM and Metropolis is polynomial in ℓ and exponential in d while the (1+1) EA is efficient only for valleys of small length. Moreover, we show that both SSWM and Metropolis can also efficiently optimize a rugged function consisting of consecutive valleys. AU - Oliveto, Pietro AU - Paixao, Tiago AU - Heredia, Jorge AU - Sudholt, Dirk AU - Trubenova, Barbora ID - 1349 T2 - Proceedings of the Genetic and Evolutionary Computation Conference 2016 TI - When non-elitism outperforms elitism for crossing fitness valleys ER -