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. 2021 Dec 23:12:803309.
doi: 10.3389/fmicb.2021.803309. eCollection 2021.

Dioctanoyl Ultrashort Tetrabasic β-Peptides Sensitize Multidrug-Resistant Gram-Negative Bacteria to Novobiocin and Rifampicin

Danyel Ramirez  1 , Liam Berry  1 , Ronald Domalaon  1 , Yanqi Li  2 , Gilbert Arthur  3 , Ayush Kumar  2 , Frank Schweizer  1   4
Affiliations

Dioctanoyl Ultrashort Tetrabasic β-Peptides Sensitize Multidrug-Resistant Gram-Negative Bacteria to Novobiocin and Rifampicin

Danyel Ramirez et al. Front Microbiol. .

Abstract

Recently reported peptidomimetics with increased resistance to trypsin were shown to sensitize priority multidrug-resistant (MDR) Gram-negative bacteria to novobiocin and rifampicin. To further optimize proteolytic stability, β-amino acid-containing derivatives of these compounds were prepared, resulting in three dioctanoyl ultrashort tetrabasic β-peptides (dUSTBβPs). The nonhemolytic dUSTBβP 3, comprised of three β3-homoarginine residues and two fatty acyl tails eight carbons long, enhanced the antibacterial activity of various antibiotics from different classes. Notably, compound 3 retained the ability to potentiate novobiocin and rifampicin in wild-type Gram-negative bacteria against MDR clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. dUSTBβP 3 reduced the minimum inhibitory concentration of novobiocin and rifampicin below their interpretative susceptibility breakpoints. Furthermore, compound 3 exhibited improved in vitro stability (86.8 ± 3.7% remaining) relative to its α-amino acid-based counterpart (39.5 ± 7.4% remaining) after a 2 h incubation in human plasma.

Keywords: Acinetobacter baumannii; Escherichia coli; Pseudomonas aeruginosa; antibiotic adjuvant; novobiocin; peptidomimetic; rifampicin; β-amino acid.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of newly synthesized dioctanoyl ultrashort tetrabasic β-peptides (dUSTBβPs) and reference compounds.
Figure 2
Figure 2
Concentration-dependent hemolytic activity of dUSTBβPs against human erythrocytes. Control used was 1% Triton X-100. Results were an average of triplicates (n = 3) ± SD. See Supplementary Tables 2, 3 for exact values of % hemolysis and SDs.
Figure 3
Figure 3
Time-kill kinetics of novobiocin alone and in combination with a fixed concentration of 8 μg/mL (6 μM) dUSTBβP 3 against (A) wild-type A. baumannii ATCC 17978 and (B) MDR A. baumannii 110193.
Figure 4
Figure 4
Time-kill kinetics of rifampicin alone and in combination with a fixed concentration of 8 μg/mL (6 μM) dUSTBβP 3 against (A) wild-type A. baumannii ATCC 17978 and (B) MDR A. baumannii 110193.
Figure 5
Figure 5
Interactions of dUSTBβP 3 at a fixed concentration of 8 μg/mL (6 μM) with different antibiotics against wild-type (A) P. aeruginosa PAO1, (B) A. baumannii ATCC 17978, and (C) E. coli ATCC 25922. FICI (FIC) ≤ 0.5 = Green; FICI > 0.5 but ≤4.0 = Yellow; and FICI > 4.0 = Red. See Supplementary Table 7 for MIC values of each combination.
Figure 6
Figure 6
Measurement of OM permeabilization by dUSTBβP 3 through the accumulation of NPN in (A) A. baumannii ATCC 17978 and (B) E. coli ATCC 25922 cells. Control used was PMBN. Results were an average of triplicates (n = 3) ± SD.
Figure 7
Figure 7
Stability profile of dUSTBβP 3 and di(C8-Arg)-Nbap-Arg-NH2 in human plasma. Results were an average of duplicates (n = 2) ± SD.
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References

    1. Akhoundsadegh N., Belanger C. R., Hancock R. E. W. (2019). Outer membrane interaction kinetics of new polymyxin B analogs in Gram-negative bacilli. Antimicrob. Agents Chemother. 63, e00935–e00919. doi: 10.1128/AAC.00935-19, PMID: - DOI - PMC - PubMed
    1. Ammeter D., Idowu T., Zhanel G. G., Schweizer F. (2019). Development of a nebramine-cyclam conjugate as an antibacterial adjuvant to potentiate β-lactam antibiotics against multidrug-resistant P. aeruginosa. J. Antibiot. 72, 816–826. doi: 10.1038/s41429-019-0221-9, PMID: - DOI - PubMed
    1. Andreev K., Bianchi C., Laursen J. S., Citterio L., Hein-Kristensen L., Gram L., et al. . (2014). Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes. Biochim. Biophys. Acta Biomembr. 1838, 2492–2502. doi: 10.1016/j.bbamem.2014.05.022, PMID: - DOI - PMC - PubMed
    1. Årdal C., Balasegaram M., Laxminarayan R., McAdams D., Outterson K., Rex J. H., et al. . (2020). Antibiotic development—economic, regulatory and societal challenges. Nat. Rev. Microbiol. 18, 267–274. doi: 10.1038/s41579-019-0293-3, PMID: - DOI - PubMed
    1. Avan I., Dennis Hall C., Katritzky A. R. (2014). Peptidomimetics via modifications of amino acids and peptide bonds. Chem. Soc. Rev. 43, 3575–3594. doi: 10.1039/c3cs60384a, PMID: - DOI - PubMed

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