Dynamic collateral sensitivity profiles highlight challenges and opportunities for optimizing antibiotic sequences

Collateral Effects ◽

Early Phases ◽

Over Time ◽

As traditional antimicrobial therapies fail at escalating rates, recent focus has shifted to evolution-based therapies to slow resistance. Collateral sensitivity-the increased susceptibility to one drug associated with evolved resistance to a different drug-offers a potentially exploitable evolutionary constraint, but the manner in which collateral effects emerge over time is not well understood. Here, we use laboratory evolution in the opportunistic pathogen E. faecalis to phenotypically characterize collateral profiles through evolutionary time. Specifically, we measure collateral profiles for 400 strain-antibiotic combinations over the course of 4 evolutionary time points as strains are selected in increasing concentrations of antibiotic. We find that collateral resistance dominates during early phases of adaptation, whereas a diverse set of collateral profiles are accessible with further selection. Using simple numerical simulations, we illustrate how these temporally dynamic profiles potentially impact sequential drug therapies. Finally, we show experimentally how dynamic collateral sensitivity relationships can create optimal dosing windows that depend on finely timed switching between drugs.

Pervasive and diverse collateral sensitivity profiles inform optimal strategies to limit antibiotic resistance

10.1101/241075 ◽

2017 ◽

Cited By ~ 2

Author(s):

Jeff Maltas ◽

Kevin B. Wood

Keyword(s):

Control Process ◽

Optimal Strategies ◽

Opportunistic Pathogen ◽

Stochastic Simulations ◽

Short Term ◽

Collateral Sensitivity ◽

Optimal Drug ◽

Drug Policies ◽

Collateral Effects ◽

Pathogen Populations

ABSTRACTEvolved resistance to one antibiotic may be associated with “collateral” sensitivity to other drugs. Here we provide an extensive quantitative characterization of collateral effects in Enterococcus faecalis, a gram-positive opportunistic pathogen. By combining parallel experimental evolution with high-throughput dose-response measurements, we measure phenotypic profiles of collateral sensitivity and resistance for a total of 900 mutant-drug combinations. We find that collateral effects are pervasive but difficult to predict, as independent populations selected by the same drug can exhibit qualitatively different profiles of collateral sensitivity as well as markedly different fitness costs. Using whole-genome sequencing of evolved populations, we identified mutations in a number of known resistance determinants, including mutations in several genes previously linked with collateral sensitivity in other species. While phenotypic drug sensitivity profiles show significant diversity, they cluster into statistically similar groups characterized by selecting drugs with similar mechanisms. To exploit the statistical structure in these resistance profiles, we develop a simple mathematical model based on a stochastic control process and use it to design optimal drug policies that assign a unique drug to every possible resistance profile. Stochastic simulations reveal that these optimal drug policies outperform intuitive cycling protocols by maintaining long-term sensitivity at the expense of short-term periods of high resistance. The approach reveals a new conceptual strategy for mitigating resistance by balancing short-term inhibition of pathogen growth with infrequent use of drugs intended to steer pathogen populations to a more vulnerable future state. Experiments in laboratory populations confirm that model-inspired sequences of four drugs reduce growth and slow adaptation relative to naive protocols involving the drugs alone, in pairwise cycles, or in four-drug uniform cycles.

Pseudomonas aeruginosa-Mediated Damage Requires Distinct Receptors at the Apical and Basolateral Surfaces of the Polarized Epithelium

Infection and Immunity ◽

10.1128/iai.01215-09 ◽

2009 ◽

Vol 78 (3) ◽

pp. 939-953 ◽

Cited By ~ 36

Author(s):

Iwona Bucior ◽

Keith Mostov ◽

Joanne N. Engel

Keyword(s):

Pseudomonas Aeruginosa ◽

Mdck Cells ◽

Three Dimensional ◽

Opportunistic Pathogen ◽

Necessary And Sufficient ◽

Plastic Surfaces ◽

Pharmacologic Inhibition ◽

Increased Susceptibility ◽

Polarized Epithelium

ABSTRACT Pseudomonas aeruginosa, an important opportunistic pathogen of humans, exploits epithelial damage to establish infection. We have rigorously explored the role of N-glycoproteins and heparan sulfate proteoglycans (HSPGs) in P. aeruginosa-mediated attachment and subsequent downstream events at the apical (AP) and basolateral (BL) surfaces of polarized epithelium. We demonstrate that the N-glycan chains at the AP surface are necessary and sufficient for binding, invasion, and cytotoxicity to kidney (MDCK) and airway (Calu-3) cells grown at various states of polarization on Transwell filters. Upregulation of N-glycosylation enhanced binding, whereas pharmacologic inhibition of N-glycosylation or infection of MDCK cells defective in N-glycosylation resulted in decreased binding. In contrast, at the BL surface, the HS moiety of HSPGs mediated P. aeruginosa binding, cytotoxicity, and invasion. In incompletely polarized epithelium, HSPG abundance was increased at the AP surface, explaining its increased susceptibility to P. aeruginosa colonization and damage. Using MDCK cells grown as three-dimensional cysts as a model for epithelial organs, we show that P. aeruginosa specifically colocalized with HS-rich areas at the BL membrane but with complex N-glycans at the AP surface. Finally, P. aeruginosa bound to HS chains and N-glycans coated on plastic surfaces, showing the highest binding affinity toward isolated HS chains. Together, these findings demonstrate that P. aeruginosa recognizes distinct receptors on the AP and BL surfaces of polarized epithelium. Changes in the composition of N-glycan chains and/or in the distribution of HSPGs may explain the enhanced susceptibility of damaged epithelium to P. aeruginosa.

Testing evolutionary constraint hypotheses with early Paleozoic gastropods

Paleobiology ◽

10.1017/s0094837300013294 ◽

1995 ◽

Vol 21 (3) ◽

pp. 248-272 ◽

Cited By ~ 109

Author(s):

Peter J. Wagner

Keyword(s):

Shell Morphology ◽

Sister Species ◽

Evolutionary Constraint ◽

Early Paleozoic ◽

Internal Anatomy ◽

Morphometric Characters ◽

Higher Taxa ◽

Phylogenetic Constraints ◽

And Function ◽

The evolution of higher taxa among early Paleozoic gastropods is similar to that among early metazoans as a whole, as higher taxa diversified rapidly and early. There are two issues pertinent to this pattern. First, were greater morphologic changes concentrated in the early phases of evolution? Second, does the pattern better fit models of increasing phylogenetic constraints or increasing ecologic restrictions? This paper presents a phylogeny-based method designed to test whether amounts of morphologic evolution decreased over time. It also explores whether the data better fits models of increasing phylogenetic (i.e., developmental or genetic) constraint or increasing ecologic restriction. Two metrics of morphologic separation (i.e., the morphologic difference between sister-species) are used: (1) Euclidean distance in morphospace and (2) transition magnitude. The latter metric is calculated by a multivariate analysis of sister-species contrasts, which determines both types and magnitudes of morphologic transitions. The advantage of using transition magnitudes is that it balances the effects of transitions that either affect more morphometric characters or occur more frequently. Both metrics indicate that larger morphologic separations between sister-species were concentrated early in gastropod evolution. Among gastropods, gross shell morphology often reflects basic trophic strategy and function whereas basic internal anatomy does not. Transition magnitudes can be broken down into transitions associated with differences in basic trophic strategies and shell functional biology (“external”), and those associated with differences in basic internal anatomy (“internal”). Internal transition magnitudes show a highly significant decrease over time (p < 10–04) whereas external transition magnitudes show a much less significant decrease over time (p < 0.10) and no significant decrease after the earliest Ordovician (p ≅ 0.50). The results therefore suggest that increasing phylogenetic constraints played a greater role in the early evolution of gastropods than did increasing ecologic ones.

Pathological and Microbiological Study of Mortality in a Captive Breeding Colony of the Endangered Lord Howe Island Stick Insect (Dryococelus australis)

Veterinary Pathology ◽

10.1177/0300985818766210 ◽

2018 ◽

Vol 55 (5) ◽

pp. 719-730

Author(s):

Christine Bayley ◽

Christina Cheng ◽

Michael Lynch

Keyword(s):

Captive Breeding ◽

Positive Culture ◽

Opportunistic Pathogen ◽

Stick Insect ◽

Innate Immune ◽

Breeding Colony ◽

Lord Howe Island ◽

Stick Insects ◽

Gross Lesions ◽

The authors describe pathological and microbiological features of mortalities in a captive breeding colony of Lord Howe Island stick insects ( Dryococelus australis) over a period of 18 months. There were 2 peaks of mortality in this period. In the first, insects presented dead with minimal premonitory signs of illness. In the second, affected insects were ataxic with contracted limbs and inability to climb or right themselves. Gross lesions were uncommon but included pigmented plaques on the gut and cloacal prolapse. Histological lesions in both outbreaks indicated a cellular innate immune response including nodulation characterized by Gram-negative bacterial bacilli entrapped within nodules of pigmented hemocytes, and melanization characterized by melanin within hemocyte nodules and around bacteria. Hemolymph culture findings varied and often yielded a mixed growth. Pure growth of Serratia marcescens was cultured in 44% of animals in Outbreak 1, while pure growth of Pseudomonas aeruginosa was cultured in 30% of animals in Outbreak 2. Cases with S. marcescens-positive culture often showed inflammation at the foregut-midgut junction. The frequency of mixed bacterial culture results did not allow firm conclusions about causality to be made, and may indicate primary bacterial infection or increased susceptibility to hemolymph colonization with an opportunistic pathogen. These findings highlight the utility of histopathology combined with ancillary testing when investigating mortality in captive insect colonies.

Handbook of Research on Blended Learning Pedagogies and Professional Development in Higher Education - Advances in Higher Education and Professional Development ◽

Virtual Learning

10.4018/978-1-5225-5557-5.ch009 ◽

2018 ◽

pp. 156-176 ◽

Cited By ~ 1

Author(s):

Jennifer L. Penland ◽

Kennard Laviers ◽

Elbert Bassham ◽

Victor Nnochiri

Keyword(s):

Higher Education ◽

Virtual Reality ◽

Distance Learning ◽

Classroom Management ◽

User Involvement ◽

Virtual Reality Technology ◽

Major Player ◽

Multi Media ◽

Virtual reality (VR) is now becoming a major player in education. When first introduced into schools, computer technology and multi-media content were riveted by its newness. Over time, more higher education institutions began to use newer technologies online or distance classes that could be taken from home. Unfortunately, many students have difficulty acquiring the same experience when learning with most classroom management software (CMS). Virtual reality technology is taking user involvement to the next level of immersion and is postured to change the landscape of education in a very significant way. This chapter examines methods of employing VR to maximize benefits to the student as well as the challenges and opportunities for using VR for distance learning. Finally, emerging research and developments in VR is discussed.

Using Selection by Nonantibiotic Stressors to Sensitize Bacteria to Antibiotics

Molecular Biology and Evolution ◽

10.1093/molbev/msz303 ◽

2019 ◽

Vol 37 (5) ◽

pp. 1394-1406 ◽

Cited By ~ 1

Author(s):

Jeff Maltas ◽

Brian Krasnick ◽

Kevin B Wood

Keyword(s):

Osmotic Stress ◽

Drug Targets ◽

Bacterial Pathogen ◽

Multidrug Efflux ◽

Collateral Sensitivity ◽

Environmental Agents ◽

Collateral Effects ◽

Selective Forces ◽

Increased Sensitivity ◽

Multiple Antibiotics

Abstract Evolutionary adaptation of bacteria to nonantibiotic selective forces, such as osmotic stress, has been previously associated with increased antibiotic resistance, but much less is known about potentially sensitizing effects of nonantibiotic stressors. In this study, we use laboratory evolution to investigate adaptation of Enterococcus faecalis, an opportunistic bacterial pathogen, to a broad collection of environmental agents, ranging from antibiotics and biocides to extreme pH and osmotic stress. We find that nonantibiotic selection frequently leads to increased sensitivity to other conditions, including multiple antibiotics. Using population sequencing and whole-genome sequencing of single isolates from the evolved populations, we identify multiple mutations in genes previously linked with resistance to the selecting conditions, including genes corresponding to known drug targets or multidrug efflux systems previously tied to collateral sensitivity. Finally, we hypothesized based on the measured sensitivity profiles that sequential rounds of antibiotic and nonantibiotic selection may lead to hypersensitive populations by harnessing the orthogonal collateral effects of particular pairs of selective forces. To test this hypothesis, we show experimentally that populations evolved to a sequence of linezolid (an oxazolidinone antibiotic) and sodium benzoate (a common preservative) exhibit increased sensitivity to more stressors than adaptation to either condition alone. The results demonstrate how sequential adaptation to drug and nondrug environments can be used to sensitize bacteria to antibiotics and highlight new potential strategies for exploiting shared constraints governing adaptation to diverse environmental challenges.

Party Change and Adaptation in Latin America

Oxford Research Encyclopedia of Politics ◽

10.1093/acrefore/9780190228637.013.1687 ◽

2020 ◽

Author(s):

Jennifer Cyr ◽

Nicolás Liendo

Keyword(s):

Latin America ◽

National Level ◽

Party Change ◽

New Parties ◽

Empirical Measures ◽

Novel Concept ◽

New Research ◽

The Impact ◽

Political parties are not what they used to be. They evolve, often in response to external motivations, but also as a function of the historical time period in which they emerge. There are several determinants of party change and adaptation in Latin America. Most importantly, multiple exogenous forces, including a shift in the economic model, the adoption of decentralization policies, and the growing political voice of minoritized groups, have challenged parties to adapt for survival. While not all parties have successfully endured, some have employed diverse strategies to do so. To be sure, new parties also emerge as a function of exogenous challenges and opportunities. In Latin America, new parties have differed in form and in function from their predecessors. The emergence of new parties represents a second type of party change that must be contemplated. Overall, parties in the 21st century look quite different from their 20th-century counterpoints. Additionally, empirical measures suggest that the dynamics of party change vary across the region and also within countries across time. A novel concept, party survival, has been elaborated to address adaptation strategies that neither lead to continued electoral success at the national level nor end in full party collapse. Indeed, several countries in the region have faced at least one crisis of representation, wherein voters defected from existing parties to vote for new parties and politicians. A new research agenda, which examines the role of resources in provoking successful party emergence and adaptation over time, provides one fruitful explanation for why parties can survive a sudden and dramatic loss of national votes. Overall, knowledge of party change and adaptation has accumulated over time. It has also evolved with respect to nuance and sophistication. Still, there is much left to be learned about party change and adaptation, including the impact new parties will have on representation, governance, and democracy more generally.

Antibiotic collateral sensitivity is contingent on the repeatability of evolution

10.1101/185892 ◽

2017 ◽

Cited By ~ 5

Author(s):

Daniel Nichol ◽

Joseph Rutter ◽

Christopher Bryant ◽

Andrea M Hujer ◽

Sai Lek ◽

...

Keyword(s):

Experimental Evolution ◽

Treatment Strategies ◽

Therapeutic Benefit ◽

Cross Resistance ◽

Health Crisis ◽

Collateral Sensitivity ◽

Drug Regimens ◽

Novel Treatment Strategies ◽

AbstractAntibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is the identification of collateral sensitivities, wherein evolution under a first drug induces susceptibility to a second. Here, we report that sequential drug regimens derived from in vitro evolution experiments may have overstated therapeutic benefit, predicting a collaterally sensitive response where cross resistance ultimately occurs. We quantify the likelihood of this phenomenon by use of a mathematical model parametrised with combinatorially complete fitness landscapes for Escherichia coli. Through experimental evolution we then verify that a second drug can indeed stochastically exhibit either increased susceptibility or increased resistance when following a first. Genetic divergence is confirmed as the driver of this differential response through targeted and whole genome sequencing. Taken together, these results highlight that the success of evolutionarily-informed therapies is predicated on a rigorous probabilistic understanding of the contingencies that arise during the evolution of drug resistance.

The Evolution of the WHO/NREVSS Influenza Surveillance System: The Challenges and Opportunities that Accompany Electronic Laboratory Data

Online Journal of Public Health Informatics ◽

10.5210/ojphi.v6i1.5179 ◽

2014 ◽

Vol 6 (1) ◽

Cited By ~ 3

Author(s):

Desiree Mustaquim

Keyword(s):

Surveillance System ◽

Laboratory Testing ◽

Laboratory Data ◽

Influenza Surveillance ◽

The Public ◽

Data Analyses ◽

Testing Data ◽

Laboratory Surveillance ◽

The WHO/NREVSS Influenza laboratory surveillance system has been in use for ~40 years. Through multiple reporting methods, partner labs can share their influenza laboratory testing data to the Influenza Divsion at CDC. Over time, this system has evolved in complexity, and the most recent enhancement has been the addition of HL7 laboratory messaging through the Public Health Laboratory Interoperability Project. This reporting has been challenging to implement, but has added great value to the system, including an increased potential for new data analyses, increased functionality, and a braoder use of the resulting data.

Exploring Potential COPD Immunosuppression Pathways Causing Increased Susceptibility for MAC Infections among COPD Patients

Clinics and Practice ◽

10.3390/clinpract11030077 ◽

2021 ◽

Vol 11 (3) ◽

pp. 619-630

Author(s):

Shafaa Munjal ◽

Shalok Munjal ◽

Jingya Gao ◽

Vishwanath Venketaraman

Keyword(s):

Mycobacterium Avium ◽

Opportunistic Pathogen ◽

Developed Countries ◽

The United States ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Susceptibility To Infection ◽

Copd Patients ◽

Respiratory Conditions ◽

Although there has been a drastic decline in the cases of Tuberculosis in the United States, the prevalence of infections caused by Mycobacterium avium Complex (MAC) has steadily increased in the past decades. Mycobacterium avium (M. avium) is one of the most abundant microorganisms in the MAC species. The mycobacterium genus is divided into two major groups: tuberculosis causing mycobacteria and non-tuberculous mycobacteria. MAC is most prominent among the non-tuberculous mycobacteria. MAC is an opportunistic pathogen that is present in soil, water, and droplets in the air. MAC infections can result in respiratory disease and can disseminate in affected patients. MAC infections are especially prevalent in patients with preexisting respiratory conditions such as Chronic Obstructive Pulmonary Disease (COPD). COPD is one of the most common lung conditions in the world with the primary cause being smoking in developed countries. COPD involves chronic inflammation of lung tissue resulting in increased susceptibility to infection. There is a lack of research regarding the pathophysiology that leads COPD patients to be susceptible to MAC infection. Our review paper therefore aims to investigate how the pathogenicity of MAC bacteria and immune decline seen in COPD patients leads to a greater susceptibility to MAC infection among COPD patients.