AcrAB efflux pump impacts on the survival of adherent-invasive Escherichia coli strain LF82 inside macrophages

Fanelli, Giulia; Pasqua, Martina; Prosseda, Gianni; Grossi, Milena; Colonna, Bianca

doi:10.1038/s41598-023-29817-0

Cited by 9 publications

(10 citation statements)

References 48 publications

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“…coli in comparison to parental strains, which is incongruent with a previous report where lack of AcrB in S. enterica reduced adhesion and invasion, supporting a relevant role of the RND efflux pump in bacterial virulence [41, 42].…”

Section: Types Of Bacterial Efflux Systemscontrasting

confidence: 61%

“…The capacity for bacterial adhesion and invasion of host cells is crucial for effective colonisation and infection [40]. A recent study found a significant reduction in adhesion and invasion in efflux pump mutants of E. coli in comparison to parental strains, which is incongruent with a previous report where lack of AcrB in S. enterica reduced adhesion and invasion, supporting a relevant role of the RND efflux pump in bacterial virulence [41,42].…”

Section: Resistance Nodulation Cell Division (Rnd) Superfamilymentioning

confidence: 92%

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Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors

Gaurav

Saini

et al. 2023

Microbiology

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The problem of antibiotic resistance among pathogenic bacteria has reached a crisis level. The treatment options against infections caused by multiple drug-resistant bacteria are shrinking gradually. The current pace of the discovery of new antibacterial entities is lagging behind the rate of development of new resistance. Efflux pumps play a central role in making a bacterium resistant to multiple antibiotics due to their ability to expel a wide range of structurally diverse compounds. Besides providing an escape from antibacterial compounds, efflux pumps are also involved in bacterial stress response, virulence, biofilm formation, and altering host physiology. Efflux pumps are unique yet challenging targets for the discovery of novel efflux pump inhibitors (EPIs). EPIs could help rejuvenate our currently dried pipeline of antibacterial drug discovery. The current article highlights the recent developments in the field of efflux pumps, challenges faced during the development of EPIs and potential approaches for their development. Additionally, this review highlights the utility of resources such as natural products and machine learning to expand our EPIs arsenal using these latest technologies.

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Section: Types Of Bacterial Efflux Systemscontrasting

confidence: 61%

Section: Resistance Nodulation Cell Division (Rnd) Superfamilymentioning

confidence: 92%

Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors

Gaurav

Saini

et al. 2023

Microbiology

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“…Interestingly, the location of the Asp-Tyr dyads in MmpL3 is analogous to that of the Asp-Asp-Lys triad in AcrB, which is known to be involved in the proton relay network, and with whom MmpLs share homologous sequences. AcrB, an acridine resistance complex is a resistance-nodulation-cell division transporter multidrug efflux pump that is involved in the virulence and pathogenesis of various bacterial pathogens (Du et al, 2018;Fay et al, 2019) Similar to MmpLs, AcrB is hypothesized to be localized to the inner membrane (Fanelli et al, 2023). Considering the homology between MmpLs and AcrB, and the high sequence and structural similarity amongst MmpL isoforms, the dynamics of the binding active site pocket of MmpL4/5 are expected to be similar to that of MmpL3.…”

Section: Computational Prediction and Validation Of The Putative Drug...mentioning

confidence: 99%

Mycobactin analogue interacting with siderophore efflux-pump protein: insights from molecular dynamics simulations and whole-cell assays

Shyam,

Thakur,

Velez

et al. 2024

Front. Antibiot.

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IntroductionIn response to continued public health emergency of antimicrobial resistance (AMR), a significant key strategy is the discovery of novel mycobacterial efflux-pump inhibitors (EPIs) as potential adjuvants in combination drug therapy. Interest in identifying new chemotypes which could potentially synergize with the existing antibiotics and can be deployed as part of a combination therapy. This strategy could delay the emergence of resistance to existing antibiotics and increase their efficacy against resistant strains of mycobacterial species. In recent decades, notable approaches have been accounted for EPI development and have resulted in the discovery of several EPIs including SQ109 and AU1235. In context, to accelerate newer EPIs with novel mode of action here we have discussed mycobactin analogues and highlighted in silico binding orientation with siderophore efflux-pump proteins MmpL4/5.Methods3-(2-hydroxyphenyl)-5-(aryl)-pyrazoline series was investigated for whole-cell efflux-pump inhibitory activity against Mycobacterium smegmatis and Mycobacterium abscessus. Machine learning and molecular dynamics were performed to construct a MmpL4/5 complex embedded in a lipid bilayer to identify the putative binding site and to predict ligand-protein binding energetics. Furthermore, the identified HIT compound was investigated in synergistic assay with bedaquiline.ResultsCompound Il, 2-(5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenol, was identified as the most potent efflux pump inhibitor against M. smegmatis in whole-cell efflux-pump investigation. Followed HIT Il employed against M. abscessus for efflux-pump inhibition investigations and notable whole-cell efflux-pump inhibitory profile has been observed. The theoretical investigations predicted compound Il to be selective towards MmpL4, with significant hydrogen bonding and π-π stacking interactions effectively blocking a critical Asp-Tyr dyad interaction network necessary for proton translocation. Compound Il with bedaquiline highlighted an additive profile against the M. abscessus pathogen.ConclusionsMD simulations and whole-cell assays are indicating potential development of compound Il as an adjunct to the existing therapeutic regimen against mycobacterial infections.

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“…The combination of H/DX with mass spectrometry was used to investigate the mechanism of inhibition by targeting the adaptor protein, AcrA. This protein is part of the resistancenodulation-cell-division (RND) efflux pumps family, which is strongly linked to resistance to a wide range of antibiotics contributing to multidrug resistance (MDR) [46][47][48]. This membrane protein is part of a tripartite complex, AcrAB-TOLC, which consists of the AcrB transporter, embedded in the inner membrane, the AcrA adapter located in the periplasm, and the channel protein TOLC responsible for the transport of substrates towards the extracellular environment.…”

Section: Hydrogen-deuterium Exchange Mass Spectrometry(h/dx-ms)mentioning

confidence: 99%

Mass Spectrometry Investigation of Some ATP-Binding Cassette (ABC) Proteins

Agostini,

Traldi,

Hamdan

2024

Medicina

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Drug resistance remains one of the main causes of poor outcome in cancer therapy. It is also becoming evident that drug resistance to both chemotherapy and to antibiotics is driven by more than one mechanism. So far, there are at least eight recognized mechanisms behind such resistance. In this review, we choose to discuss one of these mechanisms, which is known to be partially driven by a class of transmembrane proteins known as ATP-binding cassette (ABC) transporters. In normal tissues, ABC transporters protect the cells from the toxic effects of xenobiotics, whereas in tumor cells, they reduce the intracellular concentrations of anticancer drugs, which ultimately leads to the emergence of multidrug resistance (MDR). A deeper understanding of the structures and the biology of these proteins is central to current efforts to circumvent resistance to both chemotherapy, targeted therapy, and antibiotics. Understanding the biology and the function of these proteins requires detailed structural and conformational information for this class of membrane proteins. For many years, such structural information has been mainly provided by X-ray crystallography and cryo-electron microscopy. More recently, mass spectrometry-based methods assumed an important role in the area of structural and conformational characterization of this class of proteins. The contribution of this technique to structural biology has been enhanced by its combination with liquid chromatography and ion mobility, as well as more refined labelling protocols and the use of more efficient fragmentation methods, which allow the detection and localization of labile post-translational modifications. In this review, we discuss the contribution of mass spectrometry to efforts to characterize some members of the ATP-binding cassette (ABC) proteins and why such a contribution is relevant to efforts to clarify the link between the overexpression of these proteins and the most widespread mechanism of chemoresistance.

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AcrAB efflux pump impacts on the survival of adherent-invasive Escherichia coli strain LF82 inside macrophages

Cited by 9 publications

References 48 publications

Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors

Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors

Mycobactin analogue interacting with siderophore efflux-pump protein: insights from molecular dynamics simulations and whole-cell assays

Mass Spectrometry Investigation of Some ATP-Binding Cassette (ABC) Proteins

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