Mechanistic aspects of maltotriose-conjugate translocation to the Gram-negative bacteria cytoplasm

Dumont, Estelle; Vergalli, Julia; Pajović, Jelena; Bhamidimarri, Satya Prathyusha; Morante, Koldo; Wang, Jiajun; Lubriks, Dmitrijs; Sūna, Edgars; Stavenger, Robert A.; Winterhalter, Mathias; Réfrégiers, Matthieu; Pagès, Jean‐Marie

doi:10.26508/lsa.201800242

Cited by 11 publications

(32 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Low cytoplasmic concentrations were proposed to be an effect of poor transport across the inner membrane, internal degradation or an expulsion via efflux pumps such as AcrAB-TolC. It was noted that cytoplasmic concentrations of the conjugate are able to trigger activation of the maltose regulon, also upregulated in the TCATd R strain [ 46 ]. In addition to the many genes upregulated in the two pathways mentioned above, four other genes that could explain the increased resistance were found: mdaB , mqsR , mdtI and mdtJ .…”

Section: Resultsmentioning

confidence: 99%

“…Overall, this expression pattern hints towards reduced cell growth and increased persister formation [ 61 ]. Surprisingly, a set of genes encoding transporters such as chaA and lamB was also downregulated [ 46 , 62 ]. While lamB is downregulated in the TMP R isolate, it is upregulated in TCATd R .…”

Section: Resultsmentioning

confidence: 99%

“…In this isolate, we see upregulation of lamB , that enables maltose uptake across the outer membrane. Dumont and co-workers have previously described a potential role of the maltose regulon in antibiotic uptake through this maltoporin [ 46 ]. Although their investigation focused on the uptake of maltodextrin-fluorophore conjugates and lamB is a sugar-specific porin, upregulation of alternative porins, like lamB has been reported to balance the loss of general porins, like TolC [ 46 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism of Resistance Development in E. coli against TCAT, a Trimethoprim-Based Photoswitchable Antibiotic

et al. 2021

View full text Add to dashboard Cite

During the last decades, a continuous rise of multi-drug resistant pathogens has threatened antibiotic efficacy. To tackle this key challenge, novel antimicrobial therapies are needed with increased specificity for the site of infection. Photopharmacology could enable such specificity by allowing for the control of antibiotic activity with light, as exemplified by trans/cis-tetra-ortho-chloroazobenzene-trimethoprim (TCAT) conjugates. Resistance development against the on (irradiated, TCATa) and off (thermally adapted, TCATd) states of TCAT were compared to that of trimethoprim (TMP) in Escherichia coli mutant strain CS1562. Genomics and transcriptomics were used to explore the acquired resistance. Although TCAT shows TMP-like dihydrofolate reductase (DHFR) inhibition in vitro, transcriptome analyses show different responses in acquired resistance. Resistance against TCATa (on) relies on the production of exopolysaccharides and overexpression of TolC. While resistance against TCATd (off) follows a slightly different gene expression profile, both indicate hampering the entrance of the molecule into the cell. Conversely, resistance against TMP is based on alterations in cell metabolism towards a more persister-like phenotype, as well as alteration of expression levels of enzymes involved in the folate biosynthesis. This study provides a deeper understanding of the development of new therapeutic strategies and the consequences on resistance development against photopharmacological drugs.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanism of Resistance Development in E. coli against TCAT, a Trimethoprim-Based Photoswitchable Antibiotic

et al. 2021

View full text Add to dashboard Cite

show abstract

“…It was then important to identify the optimum maltodextrin scaffold to utilize in our bacterial infection imaging agent. A copious amount of work was conducted to assess the difference in internalization kinetics, stability, and retention between maltodextrins in a variety of bacterial strains 38,[42][43][44][45][46][47][48] . We conducted a comparison between the maltotriose and maltohexose analogs of our imaging agent.…”

Section: Discussionmentioning

confidence: 99%

Maltotriose-based probes for fluorescence and photoacoustic imaging of bacterial infections

et al. 2020

View full text Add to dashboard Cite

Currently, there are no non-invasive tools to accurately diagnose wound and surgical site infections before they become systemic or cause significant anatomical damage. Fluorescence and photoacoustic imaging are cost-effective imaging modalities that can be used to noninvasively diagnose bacterial infections when paired with a molecularly targeted infection imaging agent. Here, we develop a fluorescent derivative of maltotriose (Cy7-1-maltotriose), which is shown to be taken up in a variety of gram-positive and gram-negative bacterial strains in vitro. In vivo fluorescence and photoacoustic imaging studies highlight the ability of this probe to detect infection, assess infection burden, and visualize the effectiveness of antibiotic treatment in E. coli-induced myositis and a clinically relevant S. aureus wound infection murine model. In addition, we show that maltotriose is an ideal scaffold for infection imaging agents encompassing better pharmacokinetic properties and in vivo stability than other maltodextrins (e.g. maltohexose).

show abstract

“…Although biochemical information on MalT and its DNA binding to the MalT boxes are available, various mechanistic and structural details are still to be elucidated. Current understanding of how maltose regulon functions has allowed its exploitation for the selective cytoplasmic internalization of synthetic maltotriose-conjugated molecules, an example of how the maltose uptake system can be used as a self-powered molecular machine for the selective delivery of drugs and other molecules into cells [141].…”

Section: Transcriptional and Functional Regulation Of Maltose/maltodementioning

confidence: 99%

An integrated transport mechanism of the maltose ABC importer

Mächtel

Narducci

Griffith

et al. 2019

Research in Microbiology

View full text Add to dashboard Cite

ATP-binding cassette (ABC) transporters use the energy of ATP hydrolysis to transport a large diversity of molecules actively across biological membranes. A combination of biochemical, biophysical, and structural studies has established the maltose transporter MalFGK2 as one of the best characterized proteins of the ABC family. MalF and MalG are the transmembrane domains, and two MalKs form a homodimer of nucleotide-binding domains. A periplasmic maltose-binding protein (MalE) delivers maltose and other maltodextrins to the transporter, and triggers its ATPase activity. Substrate import occurs in a unidirectional manner by ATP-driven conformational changes in MalK2 that allow alternating access of the substrate-binding site in MalF to each side of the membrane. In this review, we present an integrated molecular mechanism of the transport process considering all currently available information. Furthermore, we summarize remaining inconsistencies and outline possible future routes to decipher the full mechanistic details of transport by MalEFGK2 complex and that of related importer systems.

show abstract

Mechanistic aspects of maltotriose-conjugate translocation to the Gram-negative bacteria cytoplasm

Abstract: A maltotriose-conjugate can deliver molecules into the cytoplasmic space of Gram-negative bacteria by parasitizing the maltose uptake pathway.

Cited by 11 publications

References 49 publications

Mechanism of Resistance Development in E. coli against TCAT, a Trimethoprim-Based Photoswitchable Antibiotic

Mechanism of Resistance Development in E. coli against TCAT, a Trimethoprim-Based Photoswitchable Antibiotic

Maltotriose-based probes for fluorescence and photoacoustic imaging of bacterial infections

An integrated transport mechanism of the maltose ABC importer

Contact Info

Product

Resources

About