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Graphical Abstract

Graphical Abstract

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Abstract

Long-term administration of certain macrolides is efficacious in patients with persistent pulmonary infection, despite how limited the clinically achievable concentrations are, being far below their MICs. An increase in the sub-MIC of macrolide exposure-dependent sensitivity to nitrosative stress is a typical characteristic of . However, a few clinical isolates do not respond to sub-MIC of macrolide treatment. Therefore, we examined the effects of sub-MIC of erythromycin (EM) on the sensitivity to nitrosative stress together with an efflux pump inhibitor (EPI) phenylalanine arginyl β-naphthylamide (PAβN). The sensitivity to nitrosative stress increased, suggesting that the efflux pump was involved in inhibiting the sub-MIC of macrolide effect. Analysis using efflux pump-mutant revealed that MexAB-OprM, MexXY-OprM, and MexCD-OprJ are factors in reducing the sub-MIC of macrolide effect. Since macrolides interfere with quorum sensing (QS), we demonstrated that the QS–interfering agent furanone C-30 (C-30) producing greater sensitivity to nitric oxide (NO) stress than EM. The effect of C-30 was decreased by overproduction of MexAB-OprM. To investigate whether the increase in the QS–interfering agent exposure-dependent sensitivity to nitrosative stress is characteristic of clinical isolates, we examined the viability of treated with NO. Although treatment with EM could reduce cell viability, a high variability in EM effects was observed. Conversely, C-30 was highly effective at reducing cell viability. Treatment with both C-30 and PAβN was sufficiently effective against the remaining isolates. Therefore, the combination of a QS–interfering agent and an EPI could be effective in treating infections.

Funding
This study was supported by the:
  • Japan Agency for Medical Research and Development (Award JP18jk021007)
    • Principle Award Recipient: TakeshiShimizu
  • Japan Society for the Promotion of Science (Award 20K07474)
    • Principle Award Recipient: TakeshiShimizu
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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References

  1. Høiby N. Diffuse panbronchiolitis and cystic fibrosis: East meets West. Thorax 1994; 49:531–532 [View Article] [PubMed]
    [Google Scholar]
  2. Schultz MJ. Macrolide activities beyond their antimicrobial effects: macrolides in diffuse panbronchiolitis and cystic fibrosis. J Antimicrob Chemother 2004; 54:21–28 [View Article] [PubMed]
    [Google Scholar]
  3. Fujii T, Kadota J, Kawakami K, Iida K, Shirai R et al. Long term effect of erythromycin therapy in patients with chronic Pseudomonas aeruginosa infection. Thorax 1995; 50:1246–1252 [View Article] [PubMed]
    [Google Scholar]
  4. Jaffé A, Francis J, Rosenthal M, Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998; 351:420 [View Article] [PubMed]
    [Google Scholar]
  5. Bulska M, Orszulak-Michalak D. Immunomodulatory and anti-inflammatory properties of macrolides. Curr Issues Pharm Med Sci 2014; 27:61–64 [View Article]
    [Google Scholar]
  6. Imperi F, Leoni L, Visca P. Antivirulence activity of azithromycin in Pseudomonas aeruginosa. Front Microbiol 2014; 5:178 [View Article] [PubMed]
    [Google Scholar]
  7. Leroy A-G, Caillon J, Caroff N, Broquet A, Corvec S et al. Could azithromycin be part of Pseudomonas aeruginosa acute pneumonia treatment?. Front Microbiol 2021; 12:642541 [View Article] [PubMed]
    [Google Scholar]
  8. Tateda K, Comte R, Pechere JC, Köhler T, Yamaguchi K et al. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2001; 45:1930–1933 [View Article] [PubMed]
    [Google Scholar]
  9. Wagner T, Soong G, Sokol S, Saiman L, Prince A. Effects of azithromycin on clinical isolates of Pseudomonas aeruginosa from cystic fibrosis patients. Chest 2005; 128:912–919 [View Article] [PubMed]
    [Google Scholar]
  10. Wagner VE, Bushnell D, Passador L, Brooks AI, Iglewski BH. Microarray analysis of Pseudomonas aeruginosa quorum-sensing regulons: effects of growth phase and environment. J Bacteriol 2003; 185:2080–2095 [View Article] [PubMed]
    [Google Scholar]
  11. Nalca Y, Jänsch L, Bredenbruch F, Geffers R, Buer J et al. Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PAO1: a global approach. Antimicrob Agents Chemother 2006; 50:1680–1688 [View Article] [PubMed]
    [Google Scholar]
  12. Zeng J, Zhang N, Huang B, Cai R, Wu B et al. Mechanism of azithromycin inhibition of HSL synthesis in Pseudomonas aeruginosa. Sci Rep 2016; 6:24299 [View Article] [PubMed]
    [Google Scholar]
  13. Skindersoe ME, Alhede M, Phipps R, Yang L, Jensen PO et al. Effects of antibiotics on quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2008; 52:3648–3663 [View Article] [PubMed]
    [Google Scholar]
  14. Fuqua C, Parsek MR, Greenberg EP. Regulation of gene expression by cell-to-cell communication: acyl-homoserine lactone quorum sensing. Annu Rev Genet 2001; 35:439–468 [View Article] [PubMed]
    [Google Scholar]
  15. Pearson JP, Gray KM, Passador L, Tucker KD, Eberhard A et al. Structure of the autoinducer required for expression of Pseudomonas aeruginosa virulence genes. Proc Natl Acad Sci U S A 1994; 91:197–201 [View Article] [PubMed]
    [Google Scholar]
  16. Ochsner UA, Reiser J. Autoinducer-mediated regulation of rhamnolipid biosurfactant synthesis in Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 1995; 92:6424–6428 [View Article] [PubMed]
    [Google Scholar]
  17. Gambello MJ, Iglewski BH. Cloning and characterization of the Pseudomonas aeruginosa lasR gene, a transcriptional activator of elastase expression. J Bacteriol 1991; 173:3000–3009 [View Article] [PubMed]
    [Google Scholar]
  18. Pesci EC, Milbank JB, Pearson JP, McKnight S, Kende AS et al. Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 1999; 96:11229–11234 [View Article] [PubMed]
    [Google Scholar]
  19. Pesci EC, Pearson JP, Seed PC, Iglewski BH. Regulation of las and rhl quorum sensing in Pseudomonas aeruginosa. J Bacteriol 1997; 179:3127–3132 [View Article] [PubMed]
    [Google Scholar]
  20. Rasko DA, Sperandio V. Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov 2010; 9:117–128 [View Article] [PubMed]
    [Google Scholar]
  21. Ding X, Yin B, Qian L, Zeng Z, Yang Z et al. Screening for novel quorum-sensing inhibitors to interfere with the formation of Pseudomonas aeruginosa biofilm. J Med Microbiol 2011; 60:1827–1834 [View Article] [PubMed]
    [Google Scholar]
  22. Rasmussen TB, Bjarnsholt T, Skindersoe ME, Hentzer M, Kristoffersen P et al. Screening for quorum-sensing inhibitors (QSI) by use of a novel genetic system, the QSI selector. J Bacteriol 2005; 187:1799–1814 [View Article] [PubMed]
    [Google Scholar]
  23. Hentzer M, Wu H, Andersen JB, Riedel K, Rasmussen TB et al. Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 2003; 22:3803–3815 [View Article] [PubMed]
    [Google Scholar]
  24. Kim C, Kim J, Park H-Y, Park H-J, Lee JH et al. Furanone derivatives as quorum-sensing antagonists of Pseudomonas aeruginosa. Appl Microbiol Biotechnol 2008; 80:37–47 [View Article] [PubMed]
    [Google Scholar]
  25. Yang L, Rybtke MT, Jakobsen TH, Hentzer M, Bjarnsholt T et al. Computer-aided identification of recognized drugs as Pseudomonas aeruginosa quorum-sensing inhibitors. Antimicrob Agents Chemother 2009; 53:2432–2443 [View Article] [PubMed]
    [Google Scholar]
  26. Askoura M, Mottawea W, Abujamel T, Taher I. Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa. Libyan J Med 2011; 6: [View Article] [PubMed]
    [Google Scholar]
  27. Lister PD, Wolter DJ, Hanson ND. Antibacterial-resistant Pseudomonas aeruginosa: clinical impact and complex regulation of chromosomally encoded resistance mechanisms. Clin Microbiol Rev 2009; 22:582–610 [View Article] [PubMed]
    [Google Scholar]
  28. Piddock LJV. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 2006; 19:382–402 [View Article] [PubMed]
    [Google Scholar]
  29. Li X-Z, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev 2015; 28:337–418 [View Article] [PubMed]
    [Google Scholar]
  30. Li XZ, Nikaido H, Poole K. Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob Agents Chemother 1995; 39:1948–1953 [View Article] [PubMed]
    [Google Scholar]
  31. Li XZ, Barré N, Poole K. Influence of the MexA-MexB-oprM multidrug efflux system on expression of the MexC-MexD-oprJ and MexE-MexF-oprN multidrug efflux systems in Pseudomonas aeruginosa. J Antimicrob Chemother 2000; 46:885–893 [View Article] [PubMed]
    [Google Scholar]
  32. Evans K, Adewoye L, Poole K. MexR repressor of the mexAB-oprM multidrug efflux operon of Pseudomonas aeruginosa: identification of MexR binding sites in the mexA-mexR intergenic region. J Bacteriol 2001; 183:807–812 [View Article] [PubMed]
    [Google Scholar]
  33. Cao L, Srikumar R, Poole K. MexAB-OprM hyperexpression in NalC-type multidrug-resistant Pseudomonas aeruginosa: identification and characterization of the nalC gene encoding a repressor of PA3720-PA3719. Mol Microbiol 2004; 53:1423–1436 [View Article] [PubMed]
    [Google Scholar]
  34. Sobel ML, Hocquet D, Cao L, Plesiat P, Poole K. Mutations in PA3574 (nalD) lead to increased MexAB-OprM expression and multidrug resistance in laboratory and clinical isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005; 49:1782–1786 [View Article] [PubMed]
    [Google Scholar]
  35. Daigle DM, Cao L, Fraud S, Wilke MS, Pacey A et al. Protein modulator of multidrug efflux gene expression in Pseudomonas aeruginosa. J Bacteriol 2007; 189:5441–5451 [View Article] [PubMed]
    [Google Scholar]
  36. Starr LM, Fruci M, Poole K. Pentachlorophenol induction of the Pseudomonas aeruginosa mexAB-oprM efflux operon: involvement of repressors NalC and MexR and the antirepressor ArmR. PLoS One 2012; 7:e32684 [View Article] [PubMed]
    [Google Scholar]
  37. Morita Y, Cao L, Gould VC, Avison MB, Poole K. nalD encodes a second repressor of the mexAB-oprM multidrug efflux operon of Pseudomonas aeruginosa. J Bacteriol 2006; 188:8649–8654 [View Article] [PubMed]
    [Google Scholar]
  38. Srikumar R, Tsang E, Poole K. Contribution of the MexAB-OprM multidrug efflux system to the beta-lactam resistance of penicillin-binding protein and beta-lactamase-derepressed mutants of Pseudomonas aeruginosa. J Antimicrob Chemother 1999; 44:537–540 [View Article] [PubMed]
    [Google Scholar]
  39. Okamoto K, Gotoh N, Nishino T. Alterations of susceptibility of Pseudomonas aeruginosa by overproduction of multidrug efflux systems, MexAB-OprM, MexCD-OprJ, and MexXY/OprM to carbapenems: substrate specificities of the efflux systems. J Infect Chemother 2002; 8:371–373 [View Article] [PubMed]
    [Google Scholar]
  40. Llanes C, Köhler T, Patry I, Dehecq B, van Delden C et al. Role of the MexEF-OprN efflux system in low-level resistance of Pseudomonas aeruginosa to ciprofloxacin. Antimicrob Agents Chemother 2011; 55:5676–5684 [View Article]
    [Google Scholar]
  41. Hocquet D, Vogne C, El Garch F, Vejux A, Gotoh N et al. MexXY-OprM efflux pump is necessary for a adaptive resistance of Pseudomonas aeruginosa to aminoglycosides. Antimicrob Agents Chemother 2003; 47:1371–1375 [View Article] [PubMed]
    [Google Scholar]
  42. Masuda N, Sakagawa E, Ohya S, Gotoh N, Tsujimoto H et al. Contribution of the MexX-MexY-oprM efflux system to intrinsic resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2000; 44:2242–2246 [View Article] [PubMed]
    [Google Scholar]
  43. Morita Y, Tomida J, Kawamura Y. MexXY multidrug efflux system of Pseudomonas aeruginosa. Front Microbiol 2012; 3:408 [View Article] [PubMed]
    [Google Scholar]
  44. Cabot G, Ocampo-Sosa AA, Tubau F, Macia MD, Rodríguez C et al. Overexpression of AmpC and efflux pumps in Pseudomonas aeruginosa isolates from bloodstream infections: prevalence and impact on resistance in a Spanish multicenter study. Antimicrob Agents Chemother 2011; 55:1906–1911 [View Article]
    [Google Scholar]
  45. Llanes C, Hocquet D, Vogne C, Benali-Baitich D, Neuwirth C et al. Clinical strains of Pseudomonas aeruginosa overproducing MexAB-OprM and MexXY efflux pumps simultaneously. Antimicrob Agents Chemother 2004; 48:1797–1802 [View Article] [PubMed]
    [Google Scholar]
  46. Shigemura K, Osawa K, Kato A, Tokimatsu I, Arakawa S et al. Association of overexpression of efflux pump genes with antibiotic resistance in Pseudomonas aeruginosa strains clinically isolated from urinary tract infection patients. J Antibiot 2015; 68:568–572 [View Article] [PubMed]
    [Google Scholar]
  47. Pagès J-M, Masi M, Barbe J. Inhibitors of efflux pumps in Gram-negative bacteria. Trends Mol Med 2005; 11:382–389 [View Article] [PubMed]
    [Google Scholar]
  48. Dreier J, Ruggerone P. Interaction of antibacterial compounds with RND efflux pumps in Pseudomonas aeruginosa. Front Microbiol 2015; 6:660 [View Article] [PubMed]
    [Google Scholar]
  49. Opperman TJ, Nguyen ST. Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol 2015; 6:421 [View Article] [PubMed]
    [Google Scholar]
  50. Aron Z, Opperman TJ. Optimization of a novel series of pyranopyridine RND efflux pump inhibitors. Curr Opin Microbiol 2016; 33:1–6 [View Article] [PubMed]
    [Google Scholar]
  51. Compagne N, Vieira Da Cruz A, Müller RT, Hartkoorn RC, Flipo M et al. Update on the discovery of efflux pump inhibitors against critical priority Gram-negative bacteria. Antibiotics 2023; 12:180 [View Article] [PubMed]
    [Google Scholar]
  52. Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother 2001; 45:105–116 [View Article] [PubMed]
    [Google Scholar]
  53. MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol 1997; 15:323–350 [View Article] [PubMed]
    [Google Scholar]
  54. Bogdan C. Nitric oxide and the immune response. Nat Immunol 2001; 2:907–916 [View Article] [PubMed]
    [Google Scholar]
  55. Goretski J, Zafiriou OC, Hollocher TC. Steady-state nitric oxide concentrations during denitrification. J Biol Chem 1990; 265:11535–11538 [PubMed]
    [Google Scholar]
  56. Watmough NJ, Butland G, Cheesman MR, Moir JW, Richardson DJ et al. Nitric oxide in bacteria: synthesis and consumption. Biochim Biophys Acta 1999; 1411:456–474 [View Article] [PubMed]
    [Google Scholar]
  57. Sobko T, Reinders C, Norin E, Midtvedt T, Gustafsson LE et al. Gastrointestinal nitric oxide generation in germ-free and conventional rats. Am J Physiol Gastrointest Liver Physiol 2004; 287:G993–7 [View Article] [PubMed]
    [Google Scholar]
  58. Chin MP, Schauer DB, Deen WM. Prediction of nitric oxide concentrations in colonic crypts during inflammation. Nitric Oxide 2008; 19:266–275 [View Article] [PubMed]
    [Google Scholar]
  59. Elphick HE, Demoncheaux EA, Ritson S, Higenbottam TW, Everard ML. Exhaled nitric oxide is reduced in infants with cystic fibrosis. Thorax 2001; 56:151–152 [View Article] [PubMed]
    [Google Scholar]
  60. Jöbsis Q, Raatgeep HC, Schellekens SL, Kroesbergen A, Hop WC et al. Hydrogen peroxide and nitric oxide in exhaled air of children with cystic fibrosis during antibiotic treatment. Eur Respir J 2000; 16:95–100 [View Article] [PubMed]
    [Google Scholar]
  61. Mhanna MJ, Ferkol T, Martin RJ, Dreshaj IA, van Heeckeren AM et al. Nitric oxide deficiency contributes to impairment of airway relaxation in cystic fibrosis mice. Am J Respir Cell Mol Biol 2001; 24:621–626 [View Article] [PubMed]
    [Google Scholar]
  62. Shimizu T, Miyoshi-Akiyama T, Ogura K, Murata S, Ishige S et al. Effect of sub-MICs of macrolides on the sensitivity of Pseudomonas aeruginosa to nitrosative stress: effectiveness against P. aeruginosa with and without multidrug resistance. Antimicrob Agents Chemother 2020; 64:e01180-20 [View Article] [PubMed]
    [Google Scholar]
  63. Nozaki S, Niki H. Exonuclease III (XthA) enforces In Vivo DNA cloning of Escherichia coli to create cohesive ends. J Bacteriol 2019; 201:e00660-18 [View Article] [PubMed]
    [Google Scholar]
  64. Dumas J-L, van Delden C, Perron K, Köhler T. Analysis of antibiotic resistance gene expression in Pseudomonas aeruginosa by quantitative real-time-PCR. FEMS Microbiol Lett 2006; 254:217–225 [View Article] [PubMed]
    [Google Scholar]
  65. Purssell A, Poole K. Functional characterization of the NfxB repressor of the mexCD-oprJ multidrug efflux operon of Pseudomonas aeruginosa. Microbiology 2013; 159:2058–2073 [View Article] [PubMed]
    [Google Scholar]
  66. Lau CH-F, Fraud S, Jones M, Peterson SN, Poole K. Reduced expression of the rplU-rpmA ribosomal protein operon in mexXY-expressing pan-aminoglycoside-resistant mutants of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2012; 56:5171–5179 [View Article] [PubMed]
    [Google Scholar]
  67. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25:402–408 [View Article] [PubMed]
    [Google Scholar]
  68. Morita Y, Komori Y, Mima T, Kuroda T, Mizushima T et al. Construction of a series of mutants lacking all of the four major mex operons for multidrug efflux pumps or possessing each one of the operons from Pseudomonas aeruginosa PAO1: MexCD-OprJ is an inducible pump. FEMS Microbiol Lett 2001; 202:139–143 [View Article] [PubMed]
    [Google Scholar]
  69. Renau TE, Léger R, Flamme EM, Sangalang J, She MW et al. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J Med Chem 1999; 42:4928–4931 [View Article] [PubMed]
    [Google Scholar]
  70. Lamers RP, Cavallari JF, Burrows LL. The efflux inhibitor phenylalanine-arginine beta-naphthylamide (PAβN) permeabilizes the outer membrane of gram-negative bacteria. PLoS One 2013; 8:e60666 [View Article] [PubMed]
    [Google Scholar]
  71. Quale J, Bratu S, Gupta J, Landman D. Interplay of efflux system, ampC, and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother 2006; 50:1633–1641 [View Article] [PubMed]
    [Google Scholar]
  72. Tomás M, Doumith M, Warner M, Turton JF, Beceiro A et al. Efflux pumps, OprD porin, AmpC beta-lactamase, and multiresistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother 2010; 54:2219–2224 [View Article] [PubMed]
    [Google Scholar]
  73. Sobel ML, Neshat S, Poole K. Mutations in PA2491 (mexS) promote MexT-dependent mexEF-oprN expression and multidrug resistance in a clinical strain of Pseudomonas aeruginosa. J Bacteriol 2005; 187:1246–1253 [View Article] [PubMed]
    [Google Scholar]
  74. Hocquet D, Nordmann P, El Garch F, Cabanne L, Plésiat P. Involvement of the MexXY-OprM efflux system in emergence of cefepime resistance in clinical strains of Pseudomonas aeruginosa. Antimicrob Agents Chemother 2006; 50:1347–1351 [View Article] [PubMed]
    [Google Scholar]
  75. Jalal S, Ciofu O, Hoiby N, Gotoh N, Wretlind B. Molecular mechanisms of fluoroquinolone resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob Agents Chemother 2000; 44:710–712 [View Article] [PubMed]
    [Google Scholar]
  76. Trias J, Nikaido H. Outer membrane protein D2 catalyzes facilitated diffusion of carbapenems and penems through the outer membrane of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1990; 34:52–57 [View Article] [PubMed]
    [Google Scholar]
  77. Trias J, Nikaido H. Protein D2 channel of the Pseudomonas aeruginosa outer membrane has a binding site for basic amino acids and peptides. J Biol Chem 1990; 265:15680–15684 [PubMed]
    [Google Scholar]
  78. Fyfe C, Grossman TH, Kerstein K, Sutcliffe J. Resistance to macrolide antibiotics in Public Health Pathogens. Cold Spring Harb Perspect Med 2016; 6:a025395 [View Article] [PubMed]
    [Google Scholar]
  79. Janas A, Przybylski P. 14- and 15-membered lactone macrolides and their analogues and hybrids: structure, molecular mechanism of action and biological activity. Eur J Med Chem 2019; 182:111662 [View Article] [PubMed]
    [Google Scholar]
  80. Tenson T, Lovmar M, Ehrenberg M. The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J Mol Biol 2003; 330:1005–1014 [View Article] [PubMed]
    [Google Scholar]
  81. Yonath A. Antibiotics targeting ribosomes: resistance, selectivity, synergism and cellular regulation. Annu Rev Biochem 2005; 74:649–679 [View Article] [PubMed]
    [Google Scholar]
  82. Arsic B, Awan A, Brennan RJ, Aguilar JA, Ledder R et al. Theoretical and experimental investigation on clarithromycin, erythromycin A and azithromycin and descladinosyl derivatives of clarithromycin and azithromycin with 3-O substitution as anti-bacterial agents. Med Chem Commun 2014; 5:1347–1354 [View Article]
    [Google Scholar]
  83. Tateda K, Hirakata Y, Furuya N, Ohno A, Yamaguchi K. Effects of sub-MICs of erythromycin and other macrolide antibiotics on serum sensitivity of Pseudomonas aeruginosa. Antimicrob Agents Chemother 1993; 37:675–680 [View Article] [PubMed]
    [Google Scholar]
  84. Tateda K, Ishii Y, Matsumoto T, Furuya N, Nagashima M et al. Direct evidence for antipseudomonal activity of macrolides: exposure-dependent bactericidal activity and inhibition of protein synthesis by erythromycin, clarithromycin, and azithromycin. Antimicrob Agents Chemother 1996; 40:2271–2275 [View Article] [PubMed]
    [Google Scholar]
  85. Chalmers JD. Macrolide resistance in Pseudomonas aeruginosa: implications for practice. Eur Respir J 2017; 49:1700689 [View Article] [PubMed]
    [Google Scholar]
  86. Yoon SS, Hennigan RF, Hilliard GM, Ochsner UA, Parvatiyar K et al. Pseudomonas aeruginosa anaerobic respiration in biofilms: relationships to cystic fibrosis pathogenesis. Dev Cell 2002; 3:593–603 [View Article] [PubMed]
    [Google Scholar]
  87. Hassett DJ, Cuppoletti J, Trapnell B, Lymar SV, Rowe JJ et al. Anaerobic metabolism and quorum sensing by Pseudomonas aeruginosa biofilms in chronically infected cystic fibrosis airways: rethinking antibiotic treatment strategies and drug targets. Adv Drug Deliv Rev 2002; 54:1425–1443 [View Article] [PubMed]
    [Google Scholar]
  88. Toyofuku M, Nomura N, Fujii T, Takaya N, Maseda H et al. Quorum sensing regulates denitrification in Pseudomonas aeruginosa PAO1. J Bacteriol 2007; 189:4969–4972 [View Article] [PubMed]
    [Google Scholar]
  89. Maeda T, García-Contreras R, Pu M, Sheng L, Garcia LR et al. Quorum quenching quandary: resistance to antivirulence compounds. ISME J 2012; 6:493–501 [View Article] [PubMed]
    [Google Scholar]
  90. Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic--a vision for applied use. Biochem Pharmacol 2006; 71:910–918 [View Article] [PubMed]
    [Google Scholar]
  91. Venter H, Mowla R, Ohene-Agyei T, Ma S. RND-type drug efflux pumps from Gram-negative bacteria: molecular mechanism and inhibition. Front Microbiol 2015; 6:377 [View Article] [PubMed]
    [Google Scholar]
  92. Renau TE, Léger R, Flamme EM, Sangalang J, She MW et al. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J Med Chem 1999; 42:4928–4931 [View Article] [PubMed]
    [Google Scholar]
  93. Watkins WJ, Landaverry Y, Léger R, Litman R, Renau TE et al. The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors. Bioorg Med Chem Lett 2003; 13:4241–4244 [View Article] [PubMed]
    [Google Scholar]
  94. Plé C, Tam H-K, Vieira Da Cruz A, Compagne N, Jiménez-Castellanos J-C et al. Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps. Nat Commun 2022; 13:115 [View Article] [PubMed]
    [Google Scholar]
  95. Zhang Y, Rosado-Lugo JD, Datta P, Sun Y, Cao Y et al. Evaluation of a conformationally constrained indole carboxamide as a potential efflux pump inhibitor in Pseudomonas aeruginosa. Antibiotics (Basel) 2022; 11:716 [View Article] [PubMed]
    [Google Scholar]
  96. Stover CK, Pham XQ, Erwin AL, Mizoguchi SD, Warrener P et al. Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen. Nature 2000; 406:959–964 [View Article] [PubMed]
    [Google Scholar]
  97. Simon R, Priefer U, Pühler A. A broad host range mobilization system for In Vivo genetic engineering: transposon mutagenesis in gram negative bacteria. Nat Biotechnol 1983; 1:784–791 [View Article]
    [Google Scholar]
  98. West SE, Schweizer HP, Dall C, Sample AK, Runyen-Janecky LJ. Construction of improved Escherichia-Pseudomonas shuttle vectors derived from pUC18/19 and sequence of the region required for their replication in Pseudomonas aeruginosa. Gene 1994; 148:81–86 [View Article] [PubMed]
    [Google Scholar]
  99. Hoang TT, Karkhoff-Schweizer RR, Kutchma AJ, Schweizer HP. A broad-host-range Flp-FRT recombination system for site-specific excision of chromosomally-located DNA sequences: application for isolation of unmarked Pseudomonas aeruginosa mutants. Gene 1998; 212:77–86 [View Article] [PubMed]
    [Google Scholar]
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