Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli

Kathayat, Dipak; Helmy, Yosra A.; Deblais, Loïc; Rajashekara, Gireesh

doi:10.1038/s41598-018-33587-5

Cited by 27 publications

(60 citation statements)

References 78 publications

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“…M63 minimal media was used in the checkerboard assay as these SMs were identified as growth inhibitors in M63 media. 23 Rifampicin resistant (Rif r ) APEC O78 generated through spontaneous mutation in our previous study 23 was used for the wax moth larvae study.…”

Section: Bacterial Strains Culture Conditions and Mediamentioning

confidence: 99%

“…All the SMs (SM 1-11) used in this study were obtained from ChemBridge TM , dissolved in 100% dimethyl sulfoxide (DMSO) at 100 mM, and stored at −80°C as described previously. 23 These SMs were identified as APEC growth inhibitors in our earlier study 23 through screening of preselected enriched SM library containing 4182 SMs. Moreover, this SM library was assembled through prescreening of~81,000 compounds.…”

Section: Small Molecules and Antibioticsmentioning

confidence: 99%

“…33 These SMs possess pyrrolidinyl (SM2, SM3, and SM7), imidazole (SM4, SM5, and SM6), piperidine (SM1 and SM11), quinoline (SM8 and SM9), and nitrophenyl (SM10) scaffolds. 23 All the antibiotics used in this study (colistin sulfate salt, ciprofloxacin, and tetracycline) were purchased from Sigma-Aldrich. The selected antibiotics belong to different classes of antibacterials with different mechanisms of action and are currently being used in the poultry industry.…”

Section: Small Molecules and Antibioticsmentioning

confidence: 99%

“…13,18,20 Specifically, adjuvants can abrogate or reduce the extent of lipid A modification by reducing the expression of mcr and pmrAB/phoPQ genes; 13,18,19,21,22 thus, overcoming the colistin resistance. In this study, we investigated the adjuvant potential of previously identified membrane-acting small molecules (SMs) 23 with colistin against APEC. Because of the membrane-affecting properties of these SMs, 23 similar to previously identified colistin adjuvants which have been shown to potentiate the colistin effect by disrupting as well as permeabilizing the bacterial membrane, 19,21,24,27 these SMs can work synergistically with colistin, which is also a membrane-active antibiotic; 2 thereby, augmenting the colistin mediated disruption of the bacterial membrane.…”

Section: Introductionmentioning

confidence: 99%

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Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in Escherichia coli by Affecting pmrAB System

Kathayat

Antony

Deblais

et al. 2020

IDR

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Background: Colistin is one of the last-resort antibiotics to treat multi-drug resistant (MDR) Gram-negative bacterial infections in humans. Further, colistin has been also used to prevent and treat Enterobacteriaceae infections in food animals. However, chromosomal mutations and mobile colistin resistance (mcr) genes, which confer resistance to colistin, have been detected in bacterial isolates from food animals and humans worldwide; thus, limiting the use of colistin. Therefore, strategies that could aid in ameliorating colistin resistance are critically needed. Objective: Investigate the adjuvant potential of novel small molecules (SMs) on colistin. Materials and Methods: Previously, we identified 11 membrane-affecting SMs with bactericidal activity against avian pathogenic Escherichia coli (APEC). Here, we investigated the potentiation effect of those SMs on colistin using checkerboard assays and wax moth (Galleria mellonella) larval model. The impact of the SM combination on colistin resistance evolution was also investigated by analyzing whole genome sequences of APEC isolates passaged with colistin alone or in combination with SMs followed by quantitating pmrCAB and pmrH expression in those isolates. Results: The SM combination synergistically reduced the minimum bactericidal concentration of colistin by at least 10-fold. In larvae, the SM combination increased the efficacy of colistin by twofold with enhanced (>50%) survival and reduced (>4 logs) APEC load. Further, the SM combination decreased the frequency (5/6 to 1/6) of colistin resistance evolution and downregulated the pmrCAB and pmrH expression. Previously unknown mutations in pmrB (L14Q, T92P) and pmrA (A80V), which were predicted deleterious, were identified in the colistin-resistant (Col R) APEC isolates when passaged with colistin alone but not in combination with SMs. Our study also identified mutations in hypothetical and several phage-related proteins in Col R APEC isolates in concurrent with pmrAB mutations. Conclusion: Our study identified two SMs (SM2 and SM3) that potentiated the colistin activity and attenuated the development of colistin resistance in APEC. These SMs can be developed as anti-evolution drugs that can slow down colistin resistance development.

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Section: Bacterial Strains Culture Conditions and Mediamentioning

confidence: 99%

Section: Small Molecules and Antibioticsmentioning

confidence: 99%

Section: Small Molecules and Antibioticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in Escherichia coli by Affecting pmrAB System

Kathayat

Antony

Deblais

et al. 2020

IDR

Self Cite

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“…Escherichia coli ( E. coli ) is a normal inhabitant in the intestines of animals and humans, whereas some E. coli isolates are pathogenic and cause a variety of disease, and it is considered as one of the principal cause of morbidity and mortality in poultry ( Kathayat, et al., 2018 ). Commensal bacteria is important because they can be reservoirs of resistance determinants and because they are all more ubiquitous than pathogens ( Schaefer, et al., 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Prevalence and characteristics of extended-spectrum β-lactamases-producing Escherichia coli from broiler chickens at different day-age

et al. 2020

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Commensal Escherichia coli from the poultries have been considered as reservoirs of extended-spectrum β-lactamases ( ESBL )-encoding genes. Between May 2018 and March 2019, a total of 340 E. coli isolates were obtained from apparently healthy broiler chickens from 20 to 40 D old, distributed in 17 small-scale commercial farms. Finally, 45 isolates (8 from 20-day-old broiler chickens, 14 from 30-day-old ones, and 23 from 40-day-old ones) were identified as ESBL producers, which were further investigated to shed light on the virulence gene profiles, phylogenetic groups, and multilocus sequence types and to detect the ESBL plasmid-mediated quinolone resistance determinant ( PMQR ) genes as well as the mutations in the quinolone resistance-determining regions ( QRDR ) of gyrA and parC . Molecular analysis showed that phylogenic group A and B1 accounted for 66.7% of the ESBL producers. The overall occurrence of virulence genes ranged from 5.1% ( cva ) to 86.7% ( papC ). Twenty (44.4%) ESBL producers were considered as biofilm producers with moderate or heavy biofilm formation. The most predominant specific CTX-M subtype was bla CTX-M-14 (n = 19), followed by bla CTX-M-9 (n = 17), bla CTX-M-55 (n = 9), bla CTX-M-15 (n = 6), bla CTX-M-1 (n = 5), and bla CTX-M-65 (n = 4). Additionally, PMQR genes were identified in 86.7% of ESBL producers, qnrS (n = 21) was the most dominant PMQR gene, followed by the aac(6′)-Ib-cr (n = 15), qnrB (n = 12), and qnrA (n = 9), and all of them co-expressed with β-lactamase genes. All PMQR-positive isolates harbored simultaneously at least 1 mutation in the QRDR of gyrA and parC . Forty-five ESBL producers were assigned to 33 sequence types, and the most frequent sequence types ( STs ) was ST10 (n = 5) and followed by ST95 (n = 3). Additionally, ST302, ST88, ST410, ST187, and ST23 were represented by 2 ESBL producers, respectively, and the remaining ones exhibited diverse ST. Moreover, the prevalence of ESBL producers, the biofilm-forming ability, and the occurrence of the QRDR mutations among the E. coli isolates were characterized by gradually increased with advancing age of broiler chickens.

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In Vitro and In Vivo Evaluation of Lacticaseibacillus rhamnosus GG and Bifidobacterium lactis Bb12 Against Avian Pathogenic Escherichia coli and Identification of Novel Probiotic-Derived Bioactive Peptides

Kathayat

Closs

Helmy

et al. 2021

Probiotics & Antimicro. Prot.

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Novel small molecules affecting cell membrane as potential therapeutics for avian pathogenic Escherichia coli

Cited by 27 publications

References 78 publications

<p>Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in <em>Escherichia coli</em> by Affecting <em>pmr</em>AB System</p>

<p>Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in <em>Escherichia coli</em> by Affecting <em>pmr</em>AB System</p>

Prevalence and characteristics of extended-spectrum β-lactamases-producing Escherichia coli from broiler chickens at different day-age

In Vitro and In Vivo Evaluation of Lacticaseibacillus rhamnosus GG and Bifidobacterium lactis Bb12 Against Avian Pathogenic Escherichia coli and Identification of Novel Probiotic-Derived Bioactive Peptides

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