Pamela J. Yeh

Tackling antibiotic resistance

The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable but can nevertheless be controlled, and it must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of 30 scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, USA, from 16 to 18 May 2011. From these discussions there emerged a priority list of steps that need to be taken to resolve this global crisis.

Adaptive Phenotypic Plasticity and the Successful Colonization of a Novel Environment

Behavior and other forms of phenotypic plasticity potentially enable individuals to deal with novel situations. This implies that establishment of a population in a new environment is aided by plastic responses, as first suggested by Baldwin (1896). In the early 1980s, a small population of dark‐eyed juncos from a temperate, montane environment became established in a Mediterranean climate in coastal San Diego. The breeding season of coastal juncos is more than twice as long as that of the ancestral population, and they fledge approximately twice as many young. We investigated the adaptive significance of the longer breeding season and its consequences for population persistence. Within the coastal population, individuals with longer breeding seasons have higher offspring production and recruitment, with no measured detrimental effects such as higher mortality or lower reproductive success the following year. Population size has remained approximately constant during the 6 years of study (1998–2003). The increase in reproductive effort in the coastal population contributes substantially to the persistence of this population because there is no evidence of density‐dependent recruitment, which would otherwise negate the effects of increased fledgling production. These results provide the first quantitative support of Baldwin’s proposition that plasticity can be crucial for population persistence during the early stages of colonization.

Functional classification of drugs by properties of their pairwise interactions

Multidrug treatments are increasingly important in medicine and for probing biological systems. Although many studies have focused on interactions between specific drugs, little is known about the system properties of a full drug interaction network. Like their genetic counterparts, two drugs may have no interaction, or they may interact synergistically or antagonistically to increase or suppress their individual effects. Here we use a sensitive bioluminescence technique to provide quantitative measurements of pairwise interactions among 21 antibiotics that affect growth rate in Escherichia coli. We find that the drug interaction network possesses a special property: it can be separated into classes of drugs such that any two classes interact either purely synergistically or purely antagonistically. These classes correspond directly to the cellular functions affected by the drugs. This network approach provides a new conceptual framework for understanding the functional mechanisms of drugs and their cellular targets and can be applied in systems intractable to mutant screening, biochemistry or microscopy.

Drug interactions and the evolution of antibiotic resistance

Large-scale, systems biology approaches now allow us to systematically map synergistic and antagonistic interactions between drugs. Consequently, drug antagonism is emerging as a powerful tool to study biological function and relatedness between cellular components as well as to uncover mechanisms of drug action. Furthermore, theoretical models and new experiments suggest that antagonistic interactions between antibiotics can counteract the evolution of drug resistance.

Drug interactions modulate the potential for evolution of resistance.

Antimicrobial treatments increasingly rely on multidrug combinations, in part because of the emergence and spread of antibiotic resistance. The continued effectiveness of combination treatments depends crucially on the frequency with which multidrug resistance arises. Yet, it is unknown how this propensity for resistance depends on cross-resistance and on epistatic interactions—ranging from synergy to antagonism—between the drugs. Here, we analyzed how interactions between pairs of drugs affect the spontaneous emergence of resistance in the medically important pathogen Staphylococcus aureus. Resistance is selected for within a window of drug concentrations high enough to inhibit wild-type growth but low enough for some resistant mutants to grow. Introducing an experimental method for high-throughput colony imaging, we counted resistant colonies arising across a two-dimensional matrix of drug concentrations for each of three drug pairs. Our data show that these different drug combinations have significantly different impacts on the size of the window of drug concentrations where resistance is selected for. We framed these results in a mathematical model in which the frequencies of resistance to single drugs, cross-resistance, and epistasis combine to determine the propensity for multidrug resistance. The theory suggests that drug pairs which interact synergistically, preferred for their immediate efficacy, may in fact favor the future evolution of resistance. This framework reveals the central role of drug epistasis in the evolution of resistance and points to new strategies for combating the emergence of drug-resistant bacteria.

SOUND TRANSMISSION AND SONG DIVERGENCE: A COMPARISON OF URBAN AND FOREST ACOUSTICS

Abstract ABSTRACT Degradation of acoustic signals during transmission presents a challenging selection pressure for animals dependent on vocal communication. Sound transmission properties differ among habitats and may drive the evolution of vocal signals in different directions. Urban habitat is expanding worldwide and an increasing number of species, including many birds, must now communicate around buildings and over concrete. Urban habitats are evolutionarily new, although to some extent they may acoustically resemble rocky habitat such as cliffs and canyons. Neither urban nor these natural habitats have been studied in any detail for the selection pressure they may exert on animal communication. Dark-eyed Juncos (Junco hyemalis) commonly inhabit montane pine forests across North America, but for about 25 years an isolated population has been successfully breeding in an urban environment in southern California. We investigated potentially divergent selection pressures on junco songs, using sound transmission experiments with artificial sound stimuli, in natural forest habitat and in this urban habitat. Transmission properties differed significantly, resulting in tails of reflected sound with gradually declining amplitude in the forest and in multiple discrete echoes in the urban environment. We expected environmental selection in urban habitat to favor shorter songs with higher frequencies and slower trill rates. Despite the presence of relatively short urban songs, there was no significant shortening overall. There were also no differences in trill rates, but we did find a significantly higher minimum frequency in the urban junco population compared to three of four forest populations. Although the pattern of song divergence was not consistent and it is difficult to draw firm conclusions from this single urban population, our transmission results suggest that echoes could be important in shaping urban birdsong.

Strength of Selection Pressure Is an Important Parameter Contributing to the Complexity of Antibiotic Resistance Evolution

Revealing the genetic changes responsible for antibiotic resistance can be critical for developing novel antibiotic therapies. However, systematic studies correlating genotype to phenotype in the context of antibiotic resistance have been missing. In order to fill in this gap, we evolved 88 isogenic Escherichia coli populations against 22 antibiotics for 3 weeks. For every drug, two populations were evolved under strong selection and two populations were evolved under mild selection. By quantifying evolved populations’ resistances against all 22 drugs, we constructed two separate cross-resistance networks for strongly and mildly selected populations. Subsequently, we sequenced representative colonies isolated from evolved populations for revealing the genetic basis for novel phenotypes. Bacterial populations that evolved resistance against antibiotics under strong selection acquired high levels of cross-resistance against several antibiotics, whereas other bacterial populations evolved under milder selection acquired relatively weaker cross-resistance. In addition, we found that strongly selected strains against aminoglycosides became more susceptible to five other drug classes compared with their wild-type ancestor as a result of a point mutation on TrkH, an ion transporter protein. Our findings suggest that selection strength is an important parameter contributing to the complexity of antibiotic resistance problem and use of high doses of antibiotics to clear infections has the potential to promote increase of cross-resistance in clinics.

Patterns and coevolutionary consequences of repeated brood parasitism

The absence of adaptive host responses to virulent parasites and pathogens is paradoxical. We explored the theoretical possibility that the evolution of antiparasitic egg–ejection strategies was delayed by avian hosts lifetime experiences with brood parasitism. An analytical model indicated that individual hosts repeated exposure to parasitism decreased the relative benefits of learning–based rejecter strategies when parasitism was particularly costly. Because brood parasitic brown–headed cowbirds (Molothrus ater) and their hosts are typically philopatric across breeding attempts, spatially and temporally non–random patterns of parasitism may contribute to low levels of observed egg–ejection by vulnerable cowbird hosts. In support, we found that in three populations of two host species individual females experienced repeated cowbird parasitism during their lifetimes. We propose that repeated parasitism contributes to counterintuitive patterns of coevolutionary dynamics in spatially structured host-parasite populations.

Phenotypic Plasticity and the Evolution of a Socially Selected Trait Following Colonization of a Novel Environment

Novel selection pressures in new environments arise through two distinct processes. First, environmental conditions directly affect the fitness of different phenotypes. Second, phenotypic plasticity alters the distribution of phenotypes, thereby placing populations in new selective regimes. A small isolated population of dark‐eyed juncos Junco hyemalis became established in San Diego, probably in the early 1980s and probably from the nearby mountains. The relatively mild coastal climate has resulted in an increase in both the mean and the variance of the length of time females breed each year, and this is assumed to be a result of phenotypic plasticity. The population has evolved reduced white in the tail. We studied contemporary patterns of selection on tail white, in the context of the altered breeding season length. Late‐hatched nestlings had higher survival and were in better condition than early‐hatched nestlings, but among survivors, late‐hatched birds had less tail white. We suggest this reflects juvenile mortality favoring individuals with less tail white. In adults, we found weak sexual selection and no viability selection but positive selection on female tail white in association with fecundity. We argue that altered breeding season length had a major impact on patterns of selection and evolution in this population.

Networks from drug–drug surfaces

Mol Syst Biol. 3: 85nnMulti‐drug combinations are vital in modern medicine (Keith et al , 2005; Fitzgerald et al , 2006). Such drug combinations can also be used to probe the relationships between proteins in a network, and progress towards using drug interactions to infer network connectivity has been made in recent years. A current study by Lehar et al (2007) takes this effort a large step further by developing tools to use the entire data in a drug–drug interaction dose–response surface to give useful information on the networks in which the drug targets are embedded.nnClassically, combinations of perturbations—drugs or mutations—have been categorized into one of three interaction types: additive, synergistic, or antagonistic (Bliss, 1939; Loewe, 1953; Hartman et al , 2001). The expected null interaction is called additive, although exactly how this should be defined has been a subject of some controversy (Bliss, 1939; Loewe, 1953; Greco et al , 1995). Synergy occurs when the combination of two perturbations has an effect greater than expected from the individual effects of the single perturbations. Antagonism describes a combination with less than expected effect. These classifications have proved powerful in dissecting the modularity and connectivity of the underlying biological networks (Tong et al , 2001; Schuldiner et al , 2005; Segre et al , 2005; Yeh et al …