Defining new chemical space for drug penetration into Gram-negative bacteria

Zhao, Shibin; Adamiak, Justyna; Bonifay, Vincent; Mehla, Jitender; Zgurskaya, Helen I.; Tan, Derek S.

doi:10.1038/s41589-020-00674-6

Cited by 73 publications

(70 citation statements)

References 82 publications

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“…P. aeruginosa is intrinsically resistant to a variety of antibiotics [3]. The resistant mechanisms include low membrane permeability, multidrug efflux systems as well as chromosome encoded or horizontally acquired antibiotic breakdown or modification enzymes [4][5][6]. In addition, formation of biofilm drastically enhances the bacterial resistance to antibiotics [7].…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel phoP-phoQ Regulated Genes that Contribute to Polymyxin B Tolerance in Pseudomonas aeruginosa

et al. 2021

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Polymyxin B and E (colistin) are the last resorts to treat multidrug-resistant Gram-negative pathogens. Pseudomonas aeruginosa is intrinsically resistant to a variety of antibiotics. The PhoP-PhoQ two-component regulatory system contributes to the resistance to polymyxins by regulating an arnBCADTEF-pmrE operon that encodes lipopolysaccharide modification enzymes. To identify additional PhoP-regulated genes that contribute to the tolerance to polymyxin B, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) assay and found novel PhoP binding sites on the chromosome. We further verified that PhoP directly controls the expression of PA14_46900, PA14_50740 and PA14_52340, and the operons of PA14_11970-PA14_11960 and PA14_52350-PA14_52370. Our results demonstrated that mutation of PA14_46900 increased the bacterial binding and susceptibility to polymyxin B. Meanwhile, mutation of PA14_11960 (papP), PA14_11970 (mpl), PA14_50740 (slyB), PA14_52350 (ppgS), and PA14_52370 (ppgH) reduced the bacterial survival rates and increased ethidium bromide influx under polymyxin B or Sodium dodecyl sulfate (SDS) treatment, indicating roles of these genes in maintaining membrane integrity in response to the stresses. By 1-N-phenylnaphthylamine (NPN) and propidium iodide (PI) staining assay, we found that papP and slyB are involved in maintaining outer membrane integrity, and mpl and ppgS-ppgH are involved in maintaining inner membrane integrity. Overall, our results reveal novel PhoP-PhoQ regulated genes that contribute to polymyxin B tolerance.

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Section: Introductionmentioning

confidence: 99%

Identification of Novel phoP-phoQ Regulated Genes that Contribute to Polymyxin B Tolerance in Pseudomonas aeruginosa

et al. 2021

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“…It has been demonstrated that the increase in antibacterial agents uptake greatly enhances the antibacterial efficiency. Rapid membrane-penetrating offers straight access to bacteria chromatin and cytosol, which is followed by interrupted regulatory functions of membranes, and inactivation of proteins and DNA/RNA molecules [ 12 , 15 , 16 ]. Till now, researchers have developed several antibacterial agents that can translocate across the bacteria cell membranes using a cationic strategy based on the electrostatic attraction between the positively charged agents and negatively charged membranes [ [17] , [18] , [19] ].…”

Section: Introductionmentioning

confidence: 99%

Water-soluble PANI:PSS designed for spontaneous non-disruptive membrane penetration and direct intracellular photothermal damage on bacteria

Tang

Liu

et al. 2021

Bioactive Materials

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The major challenge in the field of antibacterial agents is to overcome the low-permeability of bacteria cell membranes that protects the cells against diverse drugs. In this work, water-soluble polyaniline (PANI)-poly (p-styrenesulfonic acid) (PSS) (PANI:PSS) is found to spontaneously penetrate bacteria cellular membranes in a non-disruptive way, leaving no evidence of membrane poration/disturbance or cell death, thus avoiding side effects caused by cationic ammonia groups in traditional ammonia-containing antibacterial agents. For aqueous synthesis, which is important for biocompatibility, the polymer is synthesized via an enzyme-mimetic route relying on the catalysis of a nanozyme. Owing to its fluorescent properties, the localization of as-prepared PANI:PSS is determined by the confocal microscope, and the results confirm its rapid entry into bacteria. Under 808 nm near-infrared (NIR) irradiation, the internalized PANI:PSS generates local hyperthermia and destroys bacteria highly efficiently from inside the cells due to its excellent photothermal effects. Staphylococcus aureus ( S. aureus ), M ethicillin-resistant Staphylococcus aureus ( MRSA ) and Escherichia coli ( E. coli ) could be effectively eliminated as well as the corresponding bacterial biofilms. Results of in vivo antibacterial experiments demonstrate excellent antibacterial activities of the water-soluble PANI:PSS without side effects. Therefore, the prepared water-soluble polymer in this study has great potential in the treatment of various bacterial infections.

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“…What evidence there is implies that there are multiple means of uptake, which is why identifying individual transporters for successful antibiotics has proven difficult [276]. On the flipside, of course, when we recognise the relevant transporters and/or their structure-activity relationships governing cell permeability, we can exploit them [437,444,[491][492][493][494][495]. Although our chief interest here relates mainly to the role of solute carriers in drug disposition, we would be remiss not to mention that, largely because they have been seriously understudied [288], SLCs themselves necessarily constitute potentially valuable and novel drug targets [11,286,[537][538][539][540][541][542][543][544][545][546][547][548][549][550][551][552].…”

Section: Transporters Antibiotics and Antimicrobial Resistance (Amr)mentioning

confidence: 99%

“…Antimicrobial resistance (AMR) is a major human health problem (e.g., [ 272 , 395 , 396 , 397 , 398 , 399 , 400 , 401 , 402 , 403 , 404 , 405 , 406 , 407 , 408 , 409 , 410 , 411 , 412 , 413 , 414 , 415 , 416 , 417 , 418 , 419 ]). Most pertinently, efflux transporters are well-recognised as a major source of AMR (e.g., [ 276 , 397 , 420 , 421 , 422 , 423 , 424 , 425 , 426 , 427 , 428 , 429 , 430 , 431 , 432 , 433 , 434 , 435 , 436 , 437 , 438 , 439 , 440 , 441 , 442 ...…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

Kell

2021

Molecules

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Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport “phospholipid bilayer transport is negligible”.

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Defining new chemical space for drug penetration into Gram-negative bacteria

Cited by 73 publications

References 82 publications

Identification of Novel phoP-phoQ Regulated Genes that Contribute to Polymyxin B Tolerance in Pseudomonas aeruginosa

Identification of Novel phoP-phoQ Regulated Genes that Contribute to Polymyxin B Tolerance in Pseudomonas aeruginosa

Water-soluble PANI:PSS designed for spontaneous non-disruptive membrane penetration and direct intracellular photothermal damage on bacteria

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

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