Bacterial effluxome as a barrier against antimicrobial agents: structural biology aspects and drug targeting

Brindangnanam, Pownraj; Sawant, Ajit Ramesh; Prashanth, K; Coumar, Mohane Selvaraj

doi:10.1080/21688370.2021.2013695

Cited by 6 publications

(4 citation statements)

References 200 publications

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“…The efflux pump AcrAB-TolC is involved in conferring CAMP resistance in different bacteria, although this is controversial in E. coli ( Blair et al., 2022 ). Overexpression of these efflux pumps also confers resistance to a variety of antibiotics ( Brindangnanam et al., 2022 ). We also found several proteins involved in ribosomal and RNA degradation, including the chaperone Hsp70 (DnaK), and 30S ribosomal proteins that have been shown to interact with the MCR-1 protein ( Supplementary Table 2 ) ( Li H. et al., 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Sporadic clone Escherichia coli ST615 as a vector and reservoir for dissemination of crucial antimicrobial resistance genes

Carrera Páez,

Olivier,

Gambino

et al. 2024

Front. Cell. Infect. Microbiol.

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There is scarce information concerning the role of sporadic clones in the dissemination of antimicrobial resistance genes (ARGs) within the nosocomial niche. We confirmed that the clinical Escherichia coli M19736 ST615 strain, one of the first isolates of Latin America that harbors a plasmid with an mcr-1 gene, could receive crucial ARG by transformation and conjugation using as donors critical plasmids that harbor blaCTX-M-15, blaKPC-2, blaNDM-5, blaNDM-1, or aadB genes. Escherichia coli M19736 acquired blaCTX-M-15, blaKPC-2, blaNDM-5, blaNDM-1, and aadB genes, being only blaNDM-1 maintained at 100% on the 10th day of subculture. In addition, when the evolved MDR-E. coli M19736 acquired sequentially blaCTX-M-15 and blaNDM-1 genes, the maintenance pattern of the plasmids changed. In addition, when the evolved XDR-E. coli M19736 acquired in an ulterior step the paadB plasmid, a different pattern of the plasmid’s maintenance was found. Interestingly, the evolved E. coli M19736 strains disseminated simultaneously the acquired conjugative plasmids in different combinations though selection was ceftazidime in all cases. Finally, we isolated and characterized the extracellular vesicles (EVs) from the native and evolved XDR-E. coli M19736 strains. Interestingly, EVs from the evolved XDR-E. coli M19736 harbored blaCTX-M-15 though the pDCAG1-CTX-M-15 was previously lost as shown by WGS and experiments, suggesting that EV could be a relevant reservoir of ARG for susceptible bacteria. These results evidenced the genetic plasticity of a sporadic clone of E. coli such as ST615 that could play a relevant transitional link in the clinical dynamics and evolution to multidrug/extensively/pandrug-resistant phenotypes of superbugs within the nosocomial niche by acting simultaneously as a vector and reservoir of multiple ARGs which later could be disseminated.

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Section: Resultsmentioning

confidence: 99%

Sporadic clone Escherichia coli ST615 as a vector and reservoir for dissemination of crucial antimicrobial resistance genes

Carrera Páez,

Olivier,

Gambino

et al. 2024

Front. Cell. Infect. Microbiol.

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“…Interestingly, we identified iscR , a transcriptional regulator of iron-sulfur cluster biogenesis, as mutation site in Klebsiella , further underlining the potential connection between NTX and iron or iron-sulfur cluster proteins. The loss of outer membrane porins and the reduction of membrane permeability in general can also be associated with AMR and has been described as mode of resistance for several antibiotic classes ( 40 – 42 ). However, NTX permeability through OmpF or OmpC was predicted to be low and respective single-knockout strains did not show any change in NTX susceptibility (Tables S2 and S3).…”

Section: Discussionmentioning

confidence: 99%

Nitroxoline resistance is associated with significant fitness loss and diminishes in vivo virulence of Escherichia coli

Deschner,

Risch,

Baier

et al. 2024

Microbiol Spectr

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Nitroxoline (NTX) is an antibiotic approved for the treatment of uncomplicated urinary tract infections (UTIs) caused by Enterobacteriaceae like Escherichia coli , and it has been on the market for more than 50 years. Despite being in use longer than several other clinically relevant antibiotics, the resistance of clinical isolates against NTX has not evolved significantly. To better understand this observation, we performed a standardized in vitro evaluation of NTX in comparison to other UTI drugs with a focus on resistance development and especially their consequences. We have managed to generate low-level resistant mutants in E. coli and Klebsiella pneumoniae using a long-term exposure setup, and identified mutations in different efflux-related genes and in other pleiotropic regulators as well as the sensor histidine kinase envZ . Subsequently, mutants were characterized by metabolic and proteomic analyses confirming major effects of NTX resistance on both metabolism and differential protein expression of E. coli , which ultimately also translates into reduced in vitro motility and in vivo virulence of mutant strains as shown in a zebrafish larvae infection model. IMPORTANCE Antimicrobial resistance (AMR) poses a global threat and requires the exploration of underestimated treatment options. Nitroxoline, an effective broad-spectrum antibiotic, does not suffer from high resistance rates in the clinics but surprisingly, it is not heavily used yet. Our findings provide compelling evidence that Nitroxoline resistance renders bacteria unable to cause an infection in vivo , thereby reinvigorating the potential of Nitroxoline in combating AMR.

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“…Carbapenemase production, along with b-lactamases and porin mutations, leads to resistance. KPC enzymes play a significant role in this resistance, with different subtypes available (Pulzova et al, 2017;Chauzy et al, 2019;Brindangnanam et al, 2022). Bacteria can also use other mechanisms, like efflux pump activation and changes in drugbinding proteins, to resist carbapenems.…”

Section: Pathogenesis Of Antibiotic Resistance In Carbapenem-resistan...mentioning

confidence: 99%

Transient comparison of techniques to counter multi-drug resistant bacteria: prime modules in curation of bacterial infections

Naveed,

Waseem,

Mahkdoom

et al. 2024

Front. Antibiot.

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Multidrug-resistant organisms are bacteria that are no longer controlled or killed by specific drugs. One of two methods causes bacteria multidrug resistance (MDR); first, these bacteria may disguise multiple cell genes coding for drug resistance to a single treatment on resistance (R) plasmids. Second, increased expression of genes coding for multidrug efflux pumps, which extrude many drugs, can cause MDR. Antibiotic resistance is a big issue since some bacteria may withstand almost all antibiotics. These bacteria can cause serious sickness, making them a public health threat. Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Multidrug resistant Mycobacterium tuberculosis (TB), and CRE are gut bacteria that resist antibiotics. Antimicrobial resistance is rising worldwide, increasing clinical and community morbidity and mortality. Superbugs have made antibiotic resistance in some environmental niches even harder to control. This study introduces new medicinal plants, gene-editing methods, nanomaterials, and bacterial vaccines that will fight MDR bacteria in the future.

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Bacterial effluxome as a barrier against antimicrobial agents: structural biology aspects and drug targeting

Cited by 6 publications

References 200 publications

Sporadic clone Escherichia coli ST615 as a vector and reservoir for dissemination of crucial antimicrobial resistance genes

Sporadic clone Escherichia coli ST615 as a vector and reservoir for dissemination of crucial antimicrobial resistance genes

Nitroxoline resistance is associated with significant fitness loss and diminishes in vivo virulence of Escherichia coli

Transient comparison of techniques to counter multi-drug resistant bacteria: prime modules in curation of bacterial infections

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