Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Drug Collateral Sensitivity”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

15 recordsLinked to original sources
PubMed2026

Collateral sensitivity-harnessing microbial vulnerabilities as a solution to antimicrobial resistance.

Bacteria exhibit an evolutionary trade-off through their development of collateral sensitivity (CS) which allows them to resist one antibiotic while becoming more vulnerable to another. This vulnerability offers a compelling therapeutic opportunity by selecting against resistant isolates. Laboratory evolution studies, genome sequencing, deep mutagenesis and use of artificial intelligence and machine learning can design the bespoke strategy against multi-drug-resistant bacteria. This review discusses about recent studies that are rationally designed to harness this evolutionary trade-off for the development of alternative antimicrobial strategies. The translational barriers to the clinical implementation of CS are addressed and evidence-based design principles for optimization of CS-guided therapy are discussed.

Bacteria↗
PubMed1978

The activity of methyl benzoquate and clopidol against Eimeria maxima: synergy and drug resistance.

Synergy between clopidol and methyl benzoquate against Eimeria maxima was shown to be supra-additive. Collateral sensitivity to these drugs could not be demonstrated in resistant lines of this parasite. Resistance to methyl benzoquate and clopidol was not transferred when lines of E. maxima, resistant to the respective drugs, were propagated together. The failure to demonstrate this phenomenon was judged not to be due to synergy between the drugs. Attempts to induce simultaneous was readily acquired by a line of E. maxima resistant to clopidol. Induced resistance to clopidol in a methyl benzoquate-resistant line required numerous passages.

Animals↗
PubMed1979

Response of scrotal and non-scrotal vertebrate testis to the male antifertility agent alpha-chlorohydrin.

Effect of single oral dose (90 mg/kg body weight), multiple doses (90 mg/kg body weight for 7 days) or even higher doses (180-300 mg/kg body weight) of alpha-chlorohydrin on the testis-epididymis complex of dog, rat, cryptorchid rat, hedgehog, domestic fowl, lizard, frog, and toad has been studied. alpha-chlorohydrin treatment, at any dose, did not induce lesions in the testis-epididymis complex of dog and hedgehog having testis in scrotum and inguinal canal respectively. Abdominal testis of cryptorchid rat, domestic fowl, lizard, frog and toad also did not respond to alpha-chlorohydrin treatment. Lesions in normal rat testis-epididymis complex, after single oral dose of alpha-chlorohydrin, were quite prominent. Non-sensitivity of alpha-chlorohydrin to these animal species may be due to the absence of the pampiniform plexus complex in hedgehog and sub-mammalian animal species. Absence of conventional epididymis in the sub-mammalian animal species may be the additional reason of the non-sensitivity of the drug. Prominence of collateral blood vasculature in dog testis-epididymis complex and some alterations in the blood supply due to cryptorchidity in cryptorchid rat testis seems to be the reason of non-sensitivity of alpha-chlorohydrin to dog and cryptorchid rat testis. These observations confirm the hypothesis that the action of a single oral dose of alpha-chlorohydrin is associted with the blood vasculature of the testis-epididymis complex.

Animals↗
PubMed2025

Sequential antibiotic exposure restores antibiotic susceptibility.

BACKGROUND: The prevalence of antibiotic resistance continues to rise, rendering many valuable antimicrobial drugs ineffective. Pairwise cyclic antibiotic therapy, where treatment is rapidly switched between two antibiotics, has been demonstrated in vitro to limit the evolution of antibiotic resistance. However, what happens when resistance inevitably evolves to one of the drugs? METHODS: In this study, we perform over 450 evolution experiments to test the resilience of four proposed cyclic therapies. We use soft agar gradient evolution and 'flat plates' to identify resistance trade-offs that are resilient to compensatory mitigation. Resensitizations were detected by antimicrobial susceptibility assays, and their mechanistic underpinnings were elucidated via genomic and phenotypic analyses. RESULTS: Resistance evolves readily and collateral sensitivity (CS) (where resistance to drug A leads to hypersensitivity to drug B) does not hinder the evolution of multidrug resistance and does not predict or promote resensitization. However, if resistance to drug B increases susceptibility to A, a phenomenon we term backward CS, resistance to A can be reduced or even reversed. For example, we show that Escherichia coli cells frequently become hypersensitive to β-lactams upon aminoglycoside resistance acquisition, due to conflicting modifications to the proton motive force and efflux pumps. We also find for the first time that polymyxin B resistance can be entirely reversed by exposure to tigecycline, through the acquisition of compensatory mutations that reduce the fitness penalty of tigecycline resistance. CONCLUSIONS: The longevity of drug cycling protocols can be significantly improved by leveraging backwards CS to resensitize cells as antibiotic resistance evolves.

Anti-Bacterial Agents↗
PubMed1978

Clinical, toxicological, and pharmacological studies of combination chemotherapy of adenocarcinoma with adriamycin and Baker's antifolate.

Ten patients with disseminated adenocarcinoma were treated with combination chemotherapy employing Adriamycin and Baker's Antifolate (BAF). There were seven patients with lung adenocarcinoma, two of whom achieved partial remission while the remaining five had their disease stabilized. Drug toxicity to the bone marrow, gastrointestinal mucosa, and skin was dose-limiting and was greater than the known toxicities of the individual drugs. Pharmacological studies of both drugs were performed on five patients to determine whether abnormal pharmacokinetics could explain this collateral toxicity. Adriamycin plasma concentrations and disappearance seemed to be unaffected by BAF. However, BAF levels were prolonged, apparently due to an Adriamycin effect on the plasma elimination of BAF, resulting in a prolonged exposure of sensitive tissues and organs to BAF. Consequently, when BAF and Adriamycin are used in combination, appropriate dose and schedule changes must be made to avoid any potentially serious side effects.

Adenocarcinoma↗
PubMed1979

Genetic control of enhanced mutability of mitochondrial DNA and gamma-ray sensitivity in Saccharomyces cerevisiae.

Five nuclear mutants enhancing the spontaneous mutation rate of mtDNA have been isolated in Saccharomyces cerevisiae. These mutators fall into five complementation groups and are located at five genetic loci different from rad50 to rad57 loci. Three mutants (gam1, gam2, and gam4), insensitive or weakly sensitive to gamma-rays, exhibit increased frequency of spontaneous production of mutants with large deletions of the mtDNA (p-) and of all tested mitochondrial drug-resistant mutants. Two other mutants (gam3 and gam5), highly sensitive to gamma-rays, increase only the mutation rate of particular alleles of the mtDNA. The mutant gam5 enhances only the production of p- and erythromycin-resistant clones. The mutant gam3 exhibits an enhanced rate of oligomycin-resistant clones as well as a collateral increase of nuclear mutability. The existence of gam3 and gam5 mutants indicates that at least two common steps control both nuclear DNA repair and the mutability of particular alleles of the mtDNA. However, the general spontaneous mutability of the mtDNA includes at least three steps not involved in the repair of nuclear DNA, as revealed by the gam1, gam2, and gam4 mutations.

Chromosome Mapping↗
PubMed1977

Antifolate studies. Activities of 40 potential antimalarial compounds against sensitive and chlorguanide triazine resistant strains of folate-requiring bacteria and Escherichia coli.

As part of the search for new antimalarial drugs, a screening program was developed using sensitive and chlorguanide triazine (CGT, cycloguanil) resistant strains of the folate-requiring bacteria, Streptococcus faecium durans, Lactobacillus casei, and Pediococcus cerevisiae. The activities of 40 compounds have been studied against these strains and Escherichia coli. Observations have been made on the points of 50% growth inhibition, the fold increase of resistance shown to each compound by the resistant strains as compared with the parent sensitive strains, and the reversal of growth inhibition by folic acid with S. faecium and L. casei by folinic acid with P. cerevisiae and by p-aminobenzoic acid with E. coli. Comparisons have been made of the activities of the test compounds with those of the standard antimalarial antifoltes, CGT and pyrimethamine (PM), and the antibacterial results have been compared with the activities of the compounds against Plasmodium berghei infections in the mouse and against human malaria infections where data are available. Of the 17 compounds reversed by folates, five had patterns of activity similar to CGT and PM in that they were most active against S. faecium and nine compounds exhibited a different pattern, being highly active against all four test bacteria. This suggests that these latter compounds either have different pharmacokinetic properties or have additional modes of action. The three CGT-resistant organisms responded to antifolates in different ways. S. faecium (R) and P. cerevisiae (R) strains were cross resistant to 4,6-diaminotriazines, 2,4-diaminopyrimidines, 2,4-diaminoquinazolines, and active 2,4-diaminopteridines. L. casei (R) was cross resistant to the triazines but was collaterally sensitive to all the other antifolates. Most of the compounds not reversed by folates were much less inhibitory for the test organisms; they were most active against L. casei. In general, their growth inhibitory concentrations varied less for the four test organisms and the responses of the sensitive and CGTR strains were similar. However, there was some cross resistance to five compounds and some collateral sensitivity to five others. Comparison of the bacteriological data with the activities of the compounds against Plasmodium berghei in the mouse showed little correlation between the two test systems; each appears to provide independent and useful information.

Animals↗
PubMed1979

Dopamine modulation of acetylcholine release from the guinea-pig brain.

The effect of dopamine (DA) and apomorphine (Apo) on acetylcholine (ACh) release from guinea-pig brain was investigated (i) in superfused slices of cerebral cortex, caudate nucleus, tuberculum olfactorium, brain stem and (ii) in unrestrained, unanaesthetized animals, provided with epidural parietal cups. DA reduced the ACh release only from slices of caudate nucleus, whereas Apo was also effective in the cerebral cortex. DA and Apo inhibition in caudate nucleus was antagonized by spiroperidol. The injection of DA (1.5 and 5 micromoles) into the cerebral ventricles (i.c.v.) caused a late, moderate behavioural stimulation and enhanced ACh outflow from the parietal cortex. The injection of Apo, either i.c.v. or i.p., promptly elicited similar effects. Spiroperidol 0.5--2 mg/kg i.p. counteracted the behavioural stimulation by Apo and amphetamine, but unexpectedly enhanced the cortical ACh outflow, leaving unaffected the cholinergic responses to Apo and Amphetamine. These results show that DA directly hinders ACh release from the striatal cholinergic structures surviving in vitro, via classical neuroleptic-sensitive receptors. On the other hand, the enhanced cortical ACh outflow caused by DA and DA-mimetic drugs in the unanaesthetized animals is suggestive of a disinhibition of the corticopetal cholinergic neurones, via neuroleptic-insensitive mechanisms. Hence, the 'paradoxical' effect of spiroperidol might represent the consequence of the increased activity of nigral DA cells with collaterals possibly involved in the control of the ascending cholinergic pathways.

Acetylcholine↗
PubMed1979

Metabolism and effects of 5-(beta-D-ribofuranosyl)isocytosine in P815 cells.

5-(beta-D-Ribofuranosyl)isocytosine (psi l Cyd), a C-nucleoside, has been shown to be active against P815 leukemia in mice. In P815 cells treated with [2-14C]psi l Cyd, we have detected radioactivity in nucleotide fractions and in RNA and DNA. Degradation to nucleosides of the labeled triphosphate nucleotide fraction and of RNA showed that the radioactivity present was chromatographically identical to psi l Cyd. Half-saturation concentrations for the incorporation of [2-14C]psi l Cyd into the triphosphate nucleotide fraction and into RNA and DNA were 370, 280, and 94 microgram/ml, respectively, which were greater than 100-fold higher than those for tritiated cytidine. The incorporation of psi l Cyd was competitively inhibited by cytidine. Phosphorylation and incorporation of psi l Cyd into nucleic acids of P815 cells and of a P815 subline resistant to 1-beta-D-arabinofuranosylcytosine are about 2- to 20-fold higher than in P815 sublines resistant to psi l Cyd or to both 5-azacytidine and 1-beta-D-arabinofuranosylcytosine. These data suggest that the phosphorylation of psi l Cyd and possibly its incorporation into nucleic acids are essential for therapeutic activity in P815 leukemias. In vitro metabolic studies also suggest that psi l Cyd and 5-azacytidine are cross-resistant and that P815 cells resistant to psi l Cyd are collaterally sensitive to 1-beta-D-arabinofuranosylcytosine. These predictions were confirmed by therapeutic experiments carried out in mice bearing P815 leukemias.

Animals↗
PubMed1976

Synaptic organization and acetylcholine sensitivity of multiply innervated autonomic ganglion cells.

The principal cells of the mudpuppy cardiac ganglion receive synapses from three sources: vagal axons, interneurons and axon collaterals from other principal cells. The simplicity of the structural organization and the visual clarity in the living preparation provide favorable conditions for examining the function of these synapses and how different classes of synapses on the same cell influence its function. We have studied the sensitivity of the principal cells to iontophoretically applied acetylcholine--the transmitter at synapses made by the vagal axons and by postganglionic axon collaterals from other principal cells. In normal ganglia, the ACh sensitivity on the cell surface is highest at the region of synapses. Partial denervation, produced by severing the vagus nerves, results in an increased ACh sensitivity in nonsynaptic areas but does not appear to affect synaptic transmission at the remaining synapses.

Acetylcholine↗
PubMed1977

Collateral sensitivity between methylene dimethane sulfonate and halogenated methotrexate derivatives in the Yoshida sarcoma in vivo and in vitro.

A Yoshida lymphosarcoma line (YMDR8) resistant to methylene dimethane sulfonate (MDMS) showed collateral sensitivity against three halogenated methotrexates: 3'-bromomethotrexate (NSC-98580), 3'-bromo-5'-chloromethotrexate (NSC-98579), and 3',5'-dichloromethotrexate (NSC-29630); however, it was cross-resistant to methotrexate itself. Two other independently derived MDMS-resistant cell lines, YMDR7 and YMDR9, also demonstrated collateral sensitivity against 3'-bromomethotrexate, but with the latter, the origin of the "induced" sensitivity probably was not due to interference with antigenic or oncogenic properties of the cell line. When these agents were used in vivo (in Wistar rats) and in vitro, subpopulation changes within the tumor lines could be observed. The possible importance of this parameter in the development of such sensitivity is discussed.

Animals↗
PubMed1976

Pleiotropic phenotype of colchicine-resistant CHO cells: cross-resistance and collateral sensitivity.

Colchicine resistant (CHR) mutants of CHO cells with reduced permeability to colchicine display extensive cross-resistance to a number of apparently unrelated compounds including puromycin, daunomycin, emetine, ethidium bromide and gramicidin D. A positive correlation was observed between the level of cross-resistance and the relative hydrophobicity of these compounds. The mutants also showed increased (collateral) sensitivity to local anaesthetics (procaine, tetracaine, xylocaine and propanolol), steroid hormones (1-dehydrotestosterone, corticosterone and 5beta-pregnan-3,20-dione) and some Triton X compounds. In general, the degree of the pleiotropic response (cross-resistance or collateral sensitivity) correlated with the degree of colchicine resistance in mutant lines. These results are consistent with the pleiotropic phenotype being the result of the same mutation(s) which confer colchicine resistance and support a model for resistance in which the reduced permeability is assumed to be the result of an alteration in the modulation of the fluidity of the surface membrane.

Anesthetics, Local↗
PubMed1979

Prophylaxis of ventricular fibrillation after acute experimental coronary occlusion by chronic beta-adrenoceptor blockade with atenolol.

Acute occlusions of the left circumflex coronary artery were performed in open-chest dogs. A control group (n = 19) was compared with three groups (total n = 17) pretreated once daily with different doses of the cardioselective beta-blocking drug atenolol (ICI 66 082) given by mouth for 5 days. Only animals without coronary collateral vessels were examined, having a mortality rate of 100% in the control group. Arrhythmias and ventricular fibrillation during the first 30 min after coronary occlusion showed a biphasic distribution in time (phase 1a and 1b). A lower degree of beta-adrenoceptor blockade reduced the incidence of arrhythmias and ventricular fibrillation in phase 1a, but fibrillation occurred in all animals during phase 1b. A higher dose of the beta-blocking drug protected the animals from ventricular fibrillation, and arrhythmias in phase 1a were greatly reduced. At all times the ventricular fibrillation threshold in the group pretreated with atenolol was significantly higher than in the control group. In both groups a significant decrease in ventricular fibrillation threshold was found only during phase 1a. The greater sensitivity of phase 1a arrhythmias to beta-blockade and the lack of a decrease in ventricular fibrillation threshold during phase 1b might indicate differences in the genesis of arrhythmias and fibrillation in phases 1a and 1b.

Animals↗