Toxin import through the antibiotic efflux channel TolC

Housden, Nicholas G.; Webby, Melissa N.; Lowe, E.D.; El‐Baba, Tarick J.; Kaminska, Renata; Redfield, Christina; Robinson, Carol V.; Kleanthous, Colin

doi:10.1038/s41467-021-24930-y

Cited by 18 publications

(14 citation statements)

References 56 publications

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“…ARGs enrichments in human-intervened mangroves could lead to accelerated ARGs dissemination among microbes of different phylogeny through horizontal gene transfer ( Laroche et al, 2009 ; Imchen and Kumavath, 2020 ). The most abundant genes were outer membrane proteins such as TolC, which is a major outer-membrane antibiotic efflux channel in Gram-negative bacteria ( Housden et al, 2021 ); and regulatory proteins that form part of two-component system such as FleR, which is part of FleS–FleR system and has a role in intrinsic antibiotic resistance ( Gooderham and Hancock, 2009 ), or AtoC involved in resistance to aminoglycoside antibiotics through AtoC-AtoS system ( Matta et al, 2007 ; Supplementary Tables 1 – 4 ). In the case of El Palmar, the lower exposure to antibiotics results in lower gene richness and lower gene diversity ( Table 2 and Supplementary Figure 1 ), which would seem to indicate that in pristine sites the diversity of ARGs is low.…”

Section: Discussionmentioning

confidence: 99%

Insights into coastal microbial antibiotic resistome through a meta-transcriptomic approach in Yucatan

Guillén-Chable

Castro²,

Rodríguez-Escamilla³

et al. 2022

Front. Microbiol.

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Antibiotic resistance (AR) is one of the greatest human and clinical challenges associated with different pathogenic organisms. However, in recent years it has also become an environmental problem due to the widespread use of antibiotics in humans and livestock activities. The ability to resist antibiotics comes from antibiotic resistance genes (ARGs) and our understanding of their presence in coastal environments is still limited. Therefore, the objective of the present study was to explore the presence and possible differences in the microbial resistome of four sites from the Yucatan coast through the evaluation of the composition and abundance of ARGs using a high-throughput analysis of metatranscriptomic sequences. In total, 3,498 ARGs were uncovered, which participate in the resistance to tetracycline, macrolide, rifamycin, fluoroquinolone, phenicol, aminoglycoside, cephalosporin, and other antibiotics. The molecular mechanisms of these ARGs were mainly efflux pump, antibiotic target alteration and antibiotic target replacement. In the same way, ARGs were detected in the samples but showing dissimilar enrichment levels. With respect to the sampling sites, the ARGs were present in all the samples collected, either from preserved or contaminated areas. Importantly, sediments of the preserved area of Dzilam presented the second highest level of ARGs detected, probably as a consequence of the antibiotics dragged to the coast by submarine groundwater discharge. In general, the resistance to a single antibiotic was greater than multiresistance, both at the level of gene and organisms; and multiresistance in organisms is acquired mainly by recruiting different monoresistance genes. To our knowledge, this is the first study that describes and compares the resistome of different samples of the Yucatan coast. This study contributes to generating information about the current state of antibiotic resistance on the Yucatan coasts for a better understanding of ARGs dissemination and could facilitate the management of ARGs pollution in the environment.

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Section: Discussionmentioning

confidence: 99%

Insights into coastal microbial antibiotic resistome through a meta-transcriptomic approach in Yucatan

Guillén-Chable

Castro²,

Rodríguez-Escamilla³

et al. 2022

Front. Microbiol.

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“…After a transient period, growth at the colony surface is restored, and expression of resistance is resumed among growing cells at the colony surface. Unlike nutrients, active import of antibiotics is at least very rare ( Delcour, 2009 ; Sugano et al, 2010 ; Housden et al, 2021 ; Rybenkov et al, 2021 ). In our case, tetracycline diffuses slowly through the cell membrane, with a half-equilibration time of approximately 45 min ( Sigler et al, 2000 ; Reuter et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Nutrient Gradients Mediate Complex Colony-Level Antibiotic Responses in Structured Microbial Populations

et al. 2022

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Antibiotic treatments often fail to eliminate bacterial populations due to heterogeneity in how individual cells respond to the drug. In structured bacterial populations such as biofilms, bacterial metabolism and environmental transport processes lead to an emergent phenotypic structure and self-generated nutrient gradients toward the interior of the colony, which can affect cell growth, gene expression and susceptibility to the drug. Even in single cells, survival depends on a dynamic interplay between the drug’s action and the expression of resistance genes. How expression of resistance is coordinated across populations in the presence of such spatiotemporal environmental coupling remains elusive. Using a custom microfluidic device, we observe the response of spatially extended microcolonies of tetracycline-resistant E. coli to precisely defined dynamic drug regimens. We find an intricate interplay between drug-induced changes in cell growth and growth-dependent expression of resistance genes, resulting in the redistribution of metabolites and the reorganization of growth patterns. This dynamic environmental feedback affects the regulation of drug resistance differently across the colony, generating dynamic phenotypic structures that maintain colony growth during exposure to high drug concentrations and increase population-level resistance to subsequent exposures. A mathematical model linking metabolism and the regulation of gene expression is able to capture the main features of spatiotemporal colony dynamics. Uncovering the fundamental principles that govern collective mechanisms of antibiotic resistance in spatially extended populations will allow the design of optimal drug regimens to counteract them.

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“…Shortly after this work was made available, a similar structure demonstrated that KlebC, a rRNAse bacteriocin from Klebsiella pneumoniae , binds TolC from Klebsiella quasipneumoniae with a binding mode similar to that of ColE1 binding TolC ( Housden et al, 2021 ). KlebC is closed in the unbound state as confirmed by the high-resolution X-ray crystal structure, which supports our proposed conformation ( Figure 2E ), and opens into a single-pass, kinked-helix to bind to TolC.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, E. coli exposure to TolC-box-containing peptides can prevent subsequent binding and cytotoxicity of full-length colicin E1 ( Jakes, 2017 ). CD of the T domain indicates that it exists as a helical hairpin (closed hinge) in solution similar to other colicin T domains ( Wiener et al, 1997 ; Housden et al, 2021 ) and that the proline at the center of the TolC box forms its apex ( Zakharov et al, 2016 ; Housden et al, 2021 ). This measurement led to the proposal, known as the ‘pillar model,’ ( Zakharov et al, 2016 ) that the T domain inserts into the TolC barrel as a helical hairpin where the N and C-termini are pointing to the cell exterior.…”

Section: Introductionmentioning

confidence: 88%

Colicin E1 opens its hinge to plug TolC

Budiardjo

Stevens

Calkins

et al. 2022

eLife

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The double membrane architecture of Gram-negative bacteria forms a barrier that is impermeable to most extracellular threats. Bacteriocin proteins evolved to exploit the accessible, surface-exposed proteins embedded in the outer membrane to deliver cytotoxic cargo. Colicin E1 is a bacteriocin produced by, and lethal to, Escherichia coli that hijacks the outer membrane proteins TolC and BtuB to enter the cell. Here we capture the colicin E1 translocation domain inside its membrane receptor, TolC, by high-resolution cryoEM to obtain the first reported structure of a bacteriocin bound to TolC. Colicin E1 binds stably to TolC as an open hinge through the TolC pore-an architectural rearrangement from colicin E1's unbound conformation. This binding is stable in live E. coli cells as indicated by single-molecule fluorescence microscopy. Finally, colicin E1 fragments binding to TolC plug the channel, inhibiting its native efflux function as an antibiotic efflux pump and heightening susceptibility to three antibiotic classes. In addition to demonstrating that these protein fragments are useful starting points for developing novel antibiotic potentiators, this method could be expanded to other colicins to inhibit other outer membrane protein functions.

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Toxin import through the antibiotic efflux channel TolC

Cited by 18 publications

References 56 publications

Insights into coastal microbial antibiotic resistome through a meta-transcriptomic approach in Yucatan

Insights into coastal microbial antibiotic resistome through a meta-transcriptomic approach in Yucatan

Nutrient Gradients Mediate Complex Colony-Level Antibiotic Responses in Structured Microbial Populations

Colicin E1 opens its hinge to plug TolC

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