Monoterpenes as nitrofurantoin resistance modulating agents: minimal structural requirements, molecular dynamics simulations, and the effect of piperitone on the emergence of nitrofurantoin resistance in Enterobacteriaceae

Abstract

The effects of different monoterpenes and 2-cyclohexen-1-one on the antibacterial activity of nitrofurantoin against resistant Enterobacter cloacae, were compared and the minimal structural component of monoterpene required for the highest level of resistance-modulating activity was determined. Subinhibitory concentrations of all compounds tested enhanced the antibacterial activity of nitrofurantoin against E. cloacae to different extents. The highest synergistic effect was observed for the monoterpenes, like piperitone, which contained a conjugated ketone and C=C bond in their carbon ring structure. Piperitone also suppressed the emergence of nitrofurantoin-resistant strains of Enterobacteriaceae that were mutagenized by ethyl methanesulfonate. The modes of interaction of carvone, piperitone, and an enzyme inhibitor, benzoate, with nitroreductase were investigated by molecular docking and molecular dynamic (MD) simulation for 20 ns. MD simulation supported greater stability of the benzoate and monoterpene-nitroreductase (NR) complexes than of free NR. The results of this investigation are promising for the synthesis of more effective lead compounds to enhance the antibacterial activity of nitro drugs against resistant Enterobacter strains.

Kazakh Ziziphora Species as Sources of Bioactive Substances

“…Piperitone oxide (48) Z. persica (0.32%) [251] Antibacterial activity against 19 Gram-positive and Gram-negative bacterial species [252] O O Piperitone (45) Z. clinopodioides (4.18%) [11] Repellent activity against ants of the genus Crematogaster [245]; insecticidal activity against larvae of Spodoptera littoralis [246] and against Callosobruchus maculatus [247] Increase in antimicrobial activity of furazolidone and nitrofurantoin against bacteria of the family Enterobacteriaceae [248,249] Fungicidal activity against Aspergillus flavus [250] Molecules 2016, 21, 826 16 of 53…”

“…rigida (1.4%) [21] Z. clinopodioides subsp. bungeana (0.6%) [201] Piperitenone (46) Z. clinopodioides (5.3%) [11] Antibacterial activity against 52 Gram-positive and Gram-negative bacterial species, disc diffusion method [11] Insecticidal activity against Sitophilus zeamais [243] O Menthone (44) Z. clinopodioides (6.2%-13.3%) [238] Antifungal effect against C. albicans, synergy with fluconazol [239]; antimicrobial activity against tested strains of bacteria, yeast and pathogenic fungi [240,241] Insecticidal activity tested against various stored grain pests and vectors [242]; moderate insecticidal activity against Sitophilus zeamais [243] Antidepressant-like effects in an unpredictable chronic mild stress mouse model of depression [244] O Piperitone (45) Z. clinopodioides (4.18%) [11] Repellent activity against ants of the genus Crematogaster [245]; insecticidal activity against larvae of Spodoptera littoralis [246] and against Callosobruchus maculatus [247] Increase in antimicrobial activity of furazolidone and nitrofurantoin against bacteria of the family Enterobacteriaceae [248,249] Fungicidal activity against Aspergillus flavus [250] O Z. clinopodioides subsp. rigida (1.4%) [21] Z. clinopodioides subsp.…”