scholarly journals Collateral Sensitivity Interactions between Antibiotics Depend on Local Abiotic Conditions

mSystems ◽  
2021 ◽  
Author(s):  
Richard C. Allen ◽  
Katia R. Pfrunder-Cardozo ◽  
Alex R. Hall
Keyword(s):  
Cross Resistance ◽  
Genetic Changes ◽  
Abiotic Conditions ◽  
Collateral Sensitivity ◽  
Resistance Evolution

When bacteria become resistant to an antibiotic, the genetic changes involved sometimes increase (cross-resistance) or decrease (collateral sensitivity) their resistance to other antibiotics. Antibiotic combinations showing repeatable collateral sensitivity could be used in treatment to slow resistance evolution.

scholarly journals Collateral sensitivity interactions between antibiotics depend on local abiotic conditions

2020 ◽  
Author(s):  
Richard C. Allen ◽  
Katia R. Pfrunder-Cardozo ◽  
Alex R. Hall
Keyword(s):  
Escherichia Coli ◽  
Real World ◽  
Cross Resistance ◽  
Local Conditions ◽  
Abiotic Conditions ◽  
Collateral Sensitivity ◽  
Resistance Evolution ◽  
Real World Applications ◽  
Collateral Effects ◽  
Resistant Mutants

AbstractMutations conferring resistance to one antibiotic can increase (cross resistance) or decrease (collateral sensitivity) resistance to others. Drug combinations displaying collateral sensitivity could be used in treatments that slow resistance evolution. However, lab-to-clinic translation requires understanding whether collateral effects are robust across different environmental conditions. Here, we isolated and characterized resistant mutants of Escherichia coli using five antibiotics, before measuring collateral effects on resistance to other antibiotics. During both isolation and phenotyping, we varied conditions in ways relevant in nature (pH, temperature, bile). This revealed local abiotic conditions modified expression of resistance against both the antibiotic used during isolation and other antibiotics. Consequently, local conditions influenced collateral sensitivity in two ways: by favouring different sets of mutants (with different collateral sensitivities), and by modifying expression of collateral effects for individual mutants. These results place collateral sensitivity in the context of environmental variation, with important implications for translation to real-world applications.

scholarly journals Systematic Investigation of Resistance Evolution to Common Antibiotics Reveals Conserved Collateral Responses across Common Human Pathogens

2020 ◽  
Vol 65 (1) ◽  
pp. e01273-20
Author(s):  
Mari C. Rodriguez de Evgrafov ◽  
Marius Faza ◽  
Konstantinos Asimakopoulos ◽  
Morten O. A. Sommer
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Growth Conditions ◽  
Systematic Investigation ◽  
Cross Resistance ◽  
Human Pathogens ◽  
Content Type ◽  
Collateral Sensitivity ◽  
Resistance Evolution ◽  
Drug Dependent

ABSTRACTAs drug resistance continues to grow, treatment strategies that turn resistance into a disadvantage for the organism will be increasingly relied upon to treat infections and to lower the rate of multidrug resistance. The majority of work in this area has investigated how resistance evolution toward a single antibiotic effects a specific organism’s collateral response to a wide variety of antibiotics. The results of these studies have been used to identify networks of drugs which can be used to drive resistance in a particular direction. However, little is known about the extent of evolutionary conservation of these responses across species. We sought to address this knowledge gap by performing a systematic resistance evolution study of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae) under uniform growth conditions using five clinically relevant antibiotics with diverse modes of action. Evolved lineages were analyzed for collateral effects and the molecular mechanisms behind the observed phenotypes. Fourteen universal cross-resistance and two global collateral sensitivity relationships were found among the lineages. Genomic analyses revealed drug-dependent divergent and conserved evolutionary trajectories among the pathogens. Our findings suggest that collateral responses may be preserved across species. These findings may help extend the contribution of previous collateral network studies in the development of treatment strategies to address the problem of antibiotic resistance.

scholarly journals 609. Differing Genotypic Contexts Between E. coli and A. baumannii Modulate the Role of blaADC-7 in the Development of Antibiotic Collateral Sensitivity

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S284-S285
Author(s):  
Erin McClure ◽  
Julia Newman ◽  
Nikhil Krishnan ◽  
Joseph Rutter ◽  
Andrea M Hujer ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Fold Increase ◽  
Protein Product ◽  
Coli Strain ◽  
Fourth Generation ◽  
Clinical Strain ◽  
Health Crisis ◽  
E Coli ◽  
Collateral Sensitivity ◽  
Resistance Evolution

Abstract Background Antibiotic resistance is a global health crisis. While persistent drug discovery of novel antibiotics has previously been relied upon to thwart resistance, evolution inevitably perseveres. While genes conferring antibiotic resistance have previously been characterized, it is unclear how varying genetic contexts can change the antibiotic resistance phenotype a given gene confers. Methods The DH10B strain of E. coli was transformed with a blaADC-7 plasmid. In 12 evolutionary replicates, the modified E. coli strain and a clinical strain of A. baumannii containing the same resistance gene were passaged daily for 10 days on cefepime gradient agar plates with gradually increasing concentrations of cefepime. MICs of cefepime and a diverse set of 15 other drugs were determined for the parental strains and after the final passage passage. MIC of cefepime after intermediary passages were determined for select replicates. Lastly the blaADC-7 gene after the final passage was sequenced. Results At the end of 10 passages, collateral sensitivity in A. baumannii was observed to tigecycline and fosfomycin in 5 and 6 replicates respectively, out of 12 total. 4 out of 12 E. coli replicates displayed collateral sensitivity to minocycline (Figure 1). In the third E. coli replicate, Sanger sequencing revealed a novel S286R mutation in blaADC-7 appearing in passage seven which preceded a several log fold increase in the MIC of cefepime (Figures 2 and 3). No additional mutations were found in the other evolutionary replicates. Conclusion Patterns of resistance varied among antibiotics of the same class, (e.g., tetracyclines, fourth-generation cephalosporins) in both E. coli and A. baumannii; however, A. baumannii expressed less widespread collateral resistance than E. coli. A previously undiscovered S286R mutation in blaADC-7 coincided with a pronounced increased in resistance to cefepime. Further studies are required to determine whether this mutation gives rise to a structural change in the protein product. Given that no other mutations were found, resistance to cefepime and subsequent collateral resistance to other antibiotics may have developed due to epigenetic changes or mutations outside the blaADC-7 genes. Indeed, future experiments with whole-genome sequencing may reveal such changes. Disclosures All authors: No reported disclosures.

MODIFICATION AND INHERITANCE OF PLEIOTROPIC CROSS RESISTANCE AND COLLATERAL SENSITIVITY IN SACCHAROMYCES CEREVISIAE

Genetics ◽  
1975 ◽  
Vol 80 (3) ◽  
pp. 483-493
Author(s):  
G H Rank ◽  
A J Robertson ◽  
K L Phillips
Keyword(s):  
Ethidium Bromide ◽  
Single Gene ◽  
Nuclear Gene ◽  
Cross Resistance ◽  
Collateral Sensitivity ◽  
Increased Sensitivity ◽  
Partial Suppression ◽  
Dequalinium Chloride ◽  
Triton X ◽  
Anaerobic Pretreatment

ABSTRACT A meiotic segregant (oliPR1) was isolated with a phenotype of multiple cross resistance and collateral sensitivity. Strain oliPR1 has increased sensitivity to ethidium bromide, dequalinium chloride, acriflavin, paromomycin and neomycin, and increased resistance to oligomycin, rutamycin, venturicidin, triethyltin bromide, antimycin, carbonylcynamide-m-chlorophenylhydrazone, tetra-N-butylammonium bromide, dibenzyldimethylammonium chloride, triphenylmethylphosphonium bromide, chloramphenicol, carbomycin, tetracycline, triton-X-165 and cycloheximide. Single gene inheritance of the cross resistance and collateral sensitivity was shown by 2:2 parental ditype segregation and reversion of the complete phenotype by a spontaneous revertant. The locus conferring the oliPR1 phenotype was mapped 11.7 units from an unspecified centromere. Antibiotic resistance showed incomplete dominance, with the level of hybrid resistance dependent upon the inhibitor tested. Resistant diploids that produced four resistant ascospores were the result of mitotic recombination prior to meiosis. A partial revertant phenotype (sensitive to all inhibitors except oligomycin, antimycin and carbonylcyanide-m-chlorophenylhydrazone) was shown to be due to a single nuclear gene causing partial suppression of oliPR1. Anaerobic pretreatment, 37° and 0.5 M KCl were observed to reduce the growth of oliPR1 when challenged with seven diverse inhibitors (antimycin, carbonylcyanide-m-chlorophenylhydrazone,-chloramphenicol, cycloheximide, oligomycin, triethyltin bromide, and triphenylmethylphosphonium bromide). Resistance to cycloheximide was not altered by the [rho—] state. A revertant of oliPR1 (sensitive to the above inhibitors but resistant to ethidium bromide, paromycin and neomycin) showed anaerobic and temperature sensitization to ethidium bromide, paromomycin and neomycin. Continuous monitoring of oxygen uptake by the revertant after anaerobic pretreatment revealed that anaerobiosis sensitized respiratory adaptation of the revertant to neomycin. It is proposed that oliPR1 is a mutation resulting in the alteration of plasma membrane premeability to many diverse inhibitors.

scholarly journals Antibiotic collateral sensitivity is contingent on the repeatability of evolution

2017 ◽  
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 ◽  
Increased Susceptibility

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.

scholarly journals Evolution of Honey Resistance in Experimental Populations of Bacteria Depends on the Type of Honey, and Has no Major Side Effects for Antibiotic Susceptibility

2020 ◽  
Author(s):  
Anna M. Bischofberger ◽  
Katia R. Pfrunder Cardozo ◽  
Michael Baumgartner ◽  
Alex R. Hall
Keyword(s):  
Antibiotic Resistance ◽  
Wound Care ◽  
Single Gene ◽  
Fold Increase ◽  
Medical Application ◽  
Single Step ◽  
Cross Resistance ◽  
Serial Transfer ◽  
Collateral Sensitivity ◽  
Collateral Effects

AbstractWith rising antibiotic resistance, alternative treatments for communicable diseases are increasingly relevant. One possible alternative for some types of infections is honey, used in wound care since before 2000 BCE and more recently in licensed, medical-grade products. However, it is unclear whether medical application of honey results in the evolution of bacterial honey resistance, and whether this has collateral effects on other bacterial traits such as antibiotic resistance. Here, we used single-step screening assays and serial transfer at increasing concentrations to isolate honey-resistant mutants of Escherichia coli. We only detected bacteria with consistently increased resistance to the honey they evolved in with two of the four tested honey products, and the observed increases were small (maximum two-fold increase in IC90). Genomic sequencing and experiments with single-gene knockouts showed a key mechanism by which bacteria increased their honey resistance was by mutating genes involved in detoxifying methylglyoxal, which contributes to the antibacterial activity of Leptospermum honeys. Crucially, we found no evidence that honey adaptation conferred cross-resistance or collateral sensitivity against nine antibiotics from six different classes. These results reveal constraints on bacterial adaptation to different types of honey, improving our ability to predict downstream consequences of wider honey application in medicine.

A Comparison of the Lethal and Kinetic Effects of Doxorubicin and 4′-EPI-Doxorubicin in Vitro

1982 ◽  
Vol 68 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Bridget T. Hill ◽  
Richard D.H. Whelan
Keyword(s):  
Cell Lines ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Human Cell Lines ◽  
Lethal Effects ◽  
Collateral Sensitivity ◽  
L5178y Cell ◽  
Kinetic Effects ◽  
Resistant Cells

« In vitro » lethal and kinetic effects of 4′-epi-doxorubicin (EPI-DXR) have been established and compared with those of doxorubicin (14-hydroxy-daunorubicin, adriamycin, NSC-123127, DXR). Both drugs show comparable cytotoxicity against a range of murine and human cell lines. Cytotoxicity increases exponentially with drug concentration and with duration of exposure. EPI-DXR like DXR exerts maximal lethal effects during the late S and G2 phases of the cycle in synchronised N1L8 Syrian hamster cells. Flow microfluorimetric data and measurements of mitotic indices provide evidence of population arrest in G2 with both drugs. Responses of various drug-resistant L5178Y cell lines were similar for DXR and EPI-DXR: (i) DXR-resistant cells exhibit complete cross-resistance to EPI-DXR, (ii) vincristine-resistant cells are cross-resistant to DXR and EPI-DXR, and (iii) methotrexate-resistant and 5-fluorouracil-resistant cells show collateral sensitivity to both drugs. These studies emphasise the similarities of DXR and EPI-DXR.

scholarly journals Evolution of antibiotic cross‐resistance and collateral sensitivity in Staphylococcus epidermidis using the mutant prevention concentration and the mutant selection window

2020 ◽  
Vol 13 (4) ◽  
pp. 808-823 ◽  
Author(s):  
Natalie Ann Lozano‐Huntelman ◽  
Nina Singh ◽  
Alondra Valencia ◽  
Portia Mira ◽  
Maral Sakayan ◽  
...  
Keyword(s):  
Staphylococcus Epidermidis ◽  
Cross Resistance ◽  
Mutant Selection ◽  
Collateral Sensitivity ◽  
Selection Window ◽  
Mutant Prevention Concentration

Resistance Risk Evaluated by Metaflumizone Selection and the Effects on Toxicities Over Other Insecticides in Spodoptera exigua (Lepidoptera: Noctuidae)

2019 ◽  
Vol 112 (5) ◽  
pp. 2354-2361
Author(s):  
Xing-Xing Sun ◽  
Hong-Yang Li ◽  
Ying-Jie Jiang ◽  
Jun-Xi Zhang ◽  
Hui-Ling Gu ◽  
...  
Keyword(s):  
Spodoptera Exigua ◽  
Channel Blocker ◽  
Resistance Management ◽  
Cross Resistance ◽  
Realized Heritability ◽  
Sodium Channel Blocker ◽  
Resistance Risk ◽  
Resistance Evolution ◽  
Threshold Trait ◽  
Lepidoptera Noctuidae

Abstract Metaflumizone is a novel semicarbazone insecticide. It functions as a sodium channel blocker insecticide (SCBI) with excellent insecticidal activity on most economically important lepidopterous pests. This study assessed the resistance risk of Spodoptera exigua (Hübner) (Lepidoptera: Noctuidae) to metaflumizone in the laboratory and the effects of metaflumizone selection on toxicities to other insecticides. Spodoptera exigua collected from a field population at Huizhou in 2012 were successively challenged by metaflumizone to evaluate the risk of resistance evolution. Twelve generations of selection increased resistance to metaflumizone by 3.4-fold and threshold trait analysis revealed that the realized heritability (h2) of this resistance was 0.086. When h2 was equal to 0.086 and 90% of individuals were killed at each generation, LC50 to metaflumizone increased by 10-fold after 15 generations. The selection by metaflumizone did not increase the resistance to indoxacarb, chlorantraniliprole, spinosad, methomyl, or endosulfan, suggesting a lack of cross-resistance. However, metaflumizone challenge upheld the recession of resistance to emamectin benzoate, chlorfluazuron, and tebufenozide. The block of resistance drops by metaflumizone exposure implied a possible cross-resistance between metaflumizone and these three insecticides. These results contribute to integrated resistance management of S. exigua.

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