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. 2021 Oct 16;10(10):1258.
doi: 10.3390/antibiotics10101258.

Synergism of a Novel 1,2,4-oxadiazole-containing Derivative with Oxacillin against Methicillin-Resistant Staphylococcus aureus

Elisabetta Buommino  1 , Simona De Marino  1 , Martina Sciarretta  1 , Marialuisa Piccolo  1 , Carmen Festa  1 , Maria Valeria D'Auria  1
Affiliations

Synergism of a Novel 1,2,4-oxadiazole-containing Derivative with Oxacillin against Methicillin-Resistant Staphylococcus aureus

Elisabetta Buommino et al. Antibiotics (Basel). .

Abstract

Staphylococcusaureus is an important opportunistic pathogen that causes many infections in humans and animals. The inappropriate use of antibiotics has favored the diffusion of methicillin-resistant S. aureus (MRSA), nullifying the efforts undertaken in the discovery of antimicrobial agents. Oxadiazole heterocycles represent privileged scaffolds for the development of new drugs because of their unique bioisosteric properties, easy synthesis, and therapeutic potential. A vast number of oxadiazole-containing derivatives have been discovered as potent antibacterial agents against multidrug-resistant MRSA strains. Here, we investigate the ability of a new library of oxadiazoles to contrast the growth of Gram-positive and Gram-negative strains. The strongest antimicrobial activity was obtained with compounds 3 (4 µM) and 12 (2 µM). Compound 12, selected for further evaluation, was found to be noncytotoxic on the HaCaT cell line up to 25 µM, bactericidal, and was able to improve the activity of oxacillin against the MRSA. The highest synergistic interaction was obtained with the combination values of 0.78 μM for compound 12, and 0.06 μg/mL for oxacillin. The FIC index value of 0.396 confirms the synergistic effect of compound 12 and oxacillin. MRSA treatment with compound 12 reduced the expression of genes included in the mec operon. In conclusion, 12 inhibited the growth of the MRSA and restored the activity of oxacillin, thus resulting in a promising compound in the treatment of MRSA infection.

Keywords: 1,2,4-oxadiazole; MRSA; Staphylococcus aureus; antimicrobial activity; drug discovery; structure–activity relationship; synergistic interaction.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
1,2,4-oxadiazole derivatives generated in this study.
Figure 2
Figure 2
Structures of previously synthetized oxadiazoles (1–3).
Scheme 1
Scheme 1
General synthetic routes to access the 1,2,4-oxadiazole derivatives 3–17. Reagents and conditions: (a) NH2OH HCl, K2CO3 in CH3OH, reflux; (b) indole-4-carboxylic acid, DIPEA, HBTU in dry DMF, 140 °C.
Figure 3
Figure 3
Time-kill assay of compound 12 against S. aureus ATCC 29213 and S. aureus ATCC 43300. Each experiment is the result of three independent experiments performed in triplicate.
Figure 4
Figure 4
Relative expression of the genes of mec operons. S. aureus ATCC 43300 was treated with subinhibitory concentrations of 12 (0.39 µM) and oxacillin (OXA) (0.03 µg/mL) for 30 min. Transcript levels were monitored by RT-PCR. The data are presented as the fold change in gene expression normalized to an endogenous reference gene (16 S) and relative to the untreated. Values represent the mean ± SD for three independent experiments.
Figure 5
Figure 5
(a) Cell survival index, evaluated by the MTT assay and monitoring of live/dead cell ratio relative for the compound 12 for the HaCaT cell line following 48 h of incubation with the indicated concentration (the range 1 → 400 μM), as indicated in the legend. Data are expressed as percentage of untreated control cells and are reported as mean of five independent experiments ± SEM (n = 30); (b) IC50 values (μM), relative to the compound 12 for the HaCaT cell line following 48 h of incubation. The IC50 values are reported as mean values ± SEM (n = 30).
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