N-Nonyloxypentyl-l-Deoxynojirimycin Inhibits Growth, Biofilm Formation and Virulence Factors Expression of Staphylococcus aureus

Abstract

Staphylococcus aureus is one of the major causes of hospital- and community-associated bacterial infections throughout the world, which are difficult to treat due to the rising number of drug-resistant strains. New molecules displaying potent activity against this bacterium are urgently needed. In this study, d- and l-deoxynojirimycin (DNJ) and a small library of their N-alkyl derivatives were screened against S. aureus ATCC 29213, with the aim to identify novel candidates with inhibitory potential. Among them, N-nonyloxypentyl-l-DNJ (l-NPDNJ) proved to be the most active compound against S. aureus ATCC 29213 and its clinical isolates, with the minimum inhibitory concentration (MIC) value of 128 μg/mL. l-NPDNJ also displayed an additive effect with gentamicin and oxacillin against the gentamicin- and methicillin-resistant S. aureus isolate 00717. Sub-MIC values of l-NPDNJ affected S. aureus biofilm development in a dose-dependent manner, inducing a strong reduction in biofilm biomass. Moreover, real-time reverse transcriptase PCR analysis revealed that l-NPDNJ effectively inhibited at sub-MIC values the transcription of the spa, hla, hlb and sea virulence genes, as well as the agrA and saeR response regulator genes.

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics

“…In the subsequent ketalization step of OH groups in 10 , we used an alternative procedure to the standard protocol (PTSA, 2,2-dimethoxypropane, 2-methoxypropene) [ 48 ], in order to avoid strictly anhydrous conditions, which are typically required to limit by-product formation derived from acid-catalysed oxirane ring opening. Exploiting our longstanding expertise in the field [ 23 , 49 , 50 , 51 , 52 , 53 ], we chose the procedure involving the use of polymer-supported triphenyl phosphine (PS-TPP)/I 2 /imidazole (ImH) system as the activating agent for the protection reaction, using acetone as the acetonide source. In this case, the reaction involves the activation of acetone by the triphenylphosphonium iodide and the subsequent double attack by the diol to the activated ketone.…”

Virulence alterations in staphylococcus aureus upon treatment with the sub-inhibitory concentrations of antibiotics

“…Escober et al demonstrated that the nuclear factor-kappa B inhibitor N-[3,5-Bis(trifluoromethyl) phenyl]-5-chloro-2-hydroxybenzamide at sub-MIC of 0.0313 μg/mL can inhibit the initial cell attachment and biofilm formation of vancomycin-resistant S. aureus strain VRS1 in a dose-dependent manner [68] . The sub-MICs of other antimicrobial compounds, such as N-nonyloxypentyl-L-DNJ, N4-benzyl-N-2-phenylquinazoline-2,4-diamine, terpenoid (+)-nootkatone, chitosan, marine steroid siphonocholin, zinc oxide, and silver nanoparticles, are found to be able to inhibit the biofilm formation of diverse S. aureus strains [43] , [46] , [69] , [70] , [71] , [89] .…”

Toward the Identification of Novel Antimicrobial Agents: One-Pot Synthesis of Lipophilic Conjugates of N-Alkyl d- and l-Iminosugars

“…Recently, as part of our longstanding research program that focused on the analysis of the effect of sugar chirality in the biological properties of iminosugars [ 15 , 22 , 23 , 24 ] and other enantiomeric bioactive compounds [ 25 , 26 , 27 , 28 ], we evaluated the antimicrobial potential of d - and l -DNJ, as well as that of a small library of their N -alkyl derivatives, against Staphylococcus aureus ATCC 29,213 [ 29 ]. Our data recognize a role of the lipophilicity of iminosugars in contributing to their antibacterial activity against S. aureus more evidently for the l -enantiomers.…”

“…Our data recognize a role of the lipophilicity of iminosugars in contributing to their antibacterial activity against S. aureus more evidently for the l -enantiomers. This led to the identification of N -nonyloxypentyl- l -DNJ ( l -NPDNJ, ent - 9 Figure 3 ) as an interesting candidate, because of its capacity to affect growth, biofilm formation and virulence factor expression of S. aureus [ 29 ].…”

“…In these early synthetic efforts, we selected as iminosugars N -butyl d - and l -DNJ ( d - and l -NBDN, 2 and ent - 2 Figure 3 ) and N -nonyloxypentyl d - and l -DNJ ( d - and l -NPDNJ, 9 and ent - 9 Figure 3 ). Contrary to the aforementioned activity of the latter, the former did not display antimicrobial properties against S. aureus ATCC 29,213 [ 29 ]. In line with our assumption, we studied whether conjugation could confer antibacterial activity to otherwise ineffective N -alkyl iminosugars while improving the properties of those already bearing an antimicrobial potential.…”