4-Hydroxybenzaldehyde sensitizes Acinetobacter baumannii to amphenicols
- 163 Downloads
Bacterial metabolism modulated by environmental chemicals could alter antibiotic susceptibility. 4-Hydroxybenzaldehyde (4-HBA), which cannot support the growth of Acinetobacter baumannii, exhibited synergism only with amphenicol antibiotics including chloramphenicol (CAM) and thiamphenicol. Interestingly, this synergistic effect was not observed with other growth-supporting, structurally similar compounds such as 4-hydroxybenzoate. Transcriptomic analysis demonstrated that genes involved in protocatechuate metabolism (pca genes) and osmotic stress (bet genes) were significantly upregulated by 4-HBA and CAM treatment. The 14C-labeled CAM influx was lower in a pcaK1 (encoding a transporter of protocatechuate) deletion mutant and was higher in the pcaK1 overexpressing cells relative to that in the wild type upon 4-HBA treatment. Our kinetic data using 14C-labeled CAM clearly showed that CAM uptake is possibly through facilitated diffusion. Deletion of pcaK1 did not result in the elimination of CAM influx, indicating that CAM does not enter only through PcaK1. The amount of 4-HBA in the culture supernatant was, however, unaffected during the test conditions, validating that it was not metabolized by the bacteria. CAM resistant A. baumannii cells derived by serial passages through CAM-amended media exhibited lower level of pcaK1 gene expression. These results led us to conclude that the activation of PcaK1 transporter is probably linked to cellular CAM susceptibility. This is the first report showing a relationship between CAM influx and aromatic compound metabolism in A. baumannii.
KeywordsAcinetobacter Synergistic compound Plant extract Chloramphenicol Synergism Phenolic compound 4-Hydroxybenzaldehyde
This work was supported by a National Research Foundation of Korea (NRF) grant to WP funded by the Korean government (MSIP) (No. NRF-2017R1A2B4005838). BS was supported by a Korea University Grant.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- Anju S, Kumar NS, Krishnakumar B, Kumar BS (2015) Synergistic combination of violacein and azoles that leads to enhanced killing of major human pathogenic dermatophytic fungi Trichophyton rubrum. Front Cell Infect Microbiol 5:57. https://doi.org/10.3389/fcimb.2015.00057 CrossRefPubMedPubMedCentralGoogle Scholar
- Cohen BE (2014) Functional linkage between genes that regulate osmotic stress responses and multidrug resistance transporters: challenges and opportunities for antibiotic discovery. Antimicrob Agents Chemother 58(2):640–646. https://doi.org/10.1128/AAC.02095-13 CrossRefPubMedPubMedCentralGoogle Scholar
- Coyne S, Rosenfeld N, Lambert T, Courvalin P, Perichon B (2010) Overexpression of resistance-nodulation-cell division pump AdeFGH confers multidrug resistance in Acinetobacter baumannii. Antimicrob Agents Chemother 54(10):4389–4393. https://doi.org/10.1128/AAC.00155-10 CrossRefPubMedPubMedCentralGoogle Scholar
- Dimarco AA, Averhoff B, Ornston LN (1993) Identification of the transcriptional activator pobR and characterization of its role in the expression of pobA, the structural gene for p-hydroxybenzoate hydroxylase in Acinetobacter calcoaceticus. J Bacteriol 175(14):4499–4506. https://doi.org/10.1128/jb.175.14.4499-4506.1993 CrossRefPubMedPubMedCentralGoogle Scholar
- Gallucci MN, Oliva M, Casero C, Dambolena J, Luna A, Zygadlo J, Demo M (2009) Antimicrobial combined action of terpenes against the food-borne microorganisms Escherichia coli, Staphylococcus aureus and Bacillus cereus. Flavour Fragr J 24(6):348–354. https://doi.org/10.1002/ffj.1948 CrossRefGoogle Scholar
- Goh HM, Beatson SA, Totsika M, Moriel DG, Phan MD, Szubert J, Runnegar N, Sidjabat HE, Paterson DL, Nimmo GR, Lipman J, Schembri MA (2013) Molecular analysis of the Acinetobacter baumannii biofilm-associated protein. Appl Environ Microbiol 79(21):6535–6543. https://doi.org/10.1128/AEM.01402-13 CrossRefPubMedPubMedCentralGoogle Scholar
- Gopal R, Kim YG, Lee JH, Lee SK, Chae JD, Son BK, Seo CH, Park Y (2014) Synergistic effects and antibiofilm properties of chimeric peptides against multidrug-resistant Acinetobacter baumannii strains. Antimicrob Agents Chemother 58(3):1622–1629. https://doi.org/10.1128/AAC.02473-13 CrossRefPubMedPubMedCentralGoogle Scholar
- Harwood CS, Nichols NN, Kim MK, Ditty JL, Parales RE (1994) Identification of the pcaRKF gene cluster from Pseudomonas putida: involvement in chemotaxis, biodegradation, and transport of 4-hydroxybenzoate. J Bacteriol 176(21):6479–6488. https://doi.org/10.1128/jb.176.21.6479-6488.1994 CrossRefPubMedPubMedCentralGoogle Scholar
- Hossain MA, Park JY, Kim JY, Suh JW, Park SC (2014, 2014) Synergistic effect and antiquorum sensing activity of Nymphaea tetragona (water lily) extract. Biomed Res Int:562173. https://doi.org/10.1155/2014/562173
- Linares JF, Moreno R, Fajardo A, Martinez-Solano L, Escalante R, Rojo F, Martínez JL (2010) The global regulator Crc modulates metabolism, susceptibility to antibiotics and virulence in Pseudomonas aeruginosa. Environ Microbiol 12(12):3196–3212. https://doi.org/10.1111/j.1462-2920.2010.02292.x CrossRefPubMedGoogle Scholar
- Magnet S, Courvalin P, Lambert T (2001) Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM4454. Antimicrob Agents Chemother 45(12):3375–3380. https://doi.org/10.1128/AAC.45.12.3375-3380.2001 CrossRefPubMedPubMedCentralGoogle Scholar
- Mussi MA, Limansky AS, Viale AM (2005) Acquisition of resistance to carbapenems in multidrug-resistant clinical strains of Acinetobacter baumannii: natural insertional inactivation of a gene encoding a member of a novel family of beta-barrel outer membrane proteins. Antimicrob Agents Chemother 49(4):1432–1440. https://doi.org/10.1128/AAC.49.4.1432-1440.2005 CrossRefPubMedPubMedCentralGoogle Scholar
- Roca I, Marti S, Espinal P, Martinez P, Gibert I, Vila J (2009) CraA, a major facilitator superfamily efflux pump associated with chloramphenicol resistance in Acinetobacter baumannii. Antimicrob Agents Chemother 53(9):4013–4014. https://doi.org/10.1128/AAC.00584-09 CrossRefPubMedPubMedCentralGoogle Scholar
- Siroy A, Molle V, Lemaitre-Guillier C, Vallenet D, Pestel-Caron M, Cozzone AJ, Jouenne T, Dé E (2005) Channel formation by CarO, the carbapenem resistance-associated outer membrane protein of Acinetobacter baumannii. Antimicrob Agents Chemother 49(12):4876–4883. https://doi.org/10.1128/AAC.49.12.4876-4883.2005 CrossRefPubMedPubMedCentralGoogle Scholar
- Srinivasan VB, Rajamohan G, Gebreyes WA (2009) Role of AbeS, a novel efflux pump of the SMR family of transporters, in resistance to antimicrobial agents in Acinetobacter baumannii. Antimicrob Agents Chemother 53(12):5312–5316. https://doi.org/10.1128/AAC.00748-09 CrossRefPubMedPubMedCentralGoogle Scholar
- Su XZ, Chen J, Mizushima T, Kuroda T, Tsuchiya T (2005) AbeM, an H+-coupled Acinetobacter baumannii multidrug efflux pump belonging to the MATE family of transporters. Antimicrob Agents Chemother 49(10):4362–4364. https://doi.org/10.1128/AAC.49.10.4362-4364.2005 CrossRefPubMedPubMedCentralGoogle Scholar
- Wi YM, Choi JY, Lee JY, Kang CI, Chung DR, Peck KR, Song JH, Ko KS (2017) Antimicrobial effects of β-lactams on imipenem-resistant ceftazidime-susceptible Pseudomonas aeruginosa. Antimicrob Agents Chemother 61(6):e00054–e00017. https://doi.org/10.1128/AAC.00054-17 CrossRefPubMedPubMedCentralGoogle Scholar
- Yan N (2015) Structural biology of the major facilitator superfamily transporters. Annu Rev Biophys 44(1):257–283. https://doi.org/10.1146/annurev-biophys-060414-033901 CrossRefPubMedGoogle Scholar