New Membrane Active Antibacterial and Antiviral Amphiphiles Derived from Heterocyclic Backbone of Pyridinium-4-Aldoxime

Abstract

Quaternary ammonium salts (QAS) are irreplaceable membrane-active antimicrobial agents that have been widely used for nearly a century. Cetylpyridinium chloride (CPC) is one of the most potent QAS. However, recent data from the literature indicate that CPC activity against resistant bacterial strains is decreasing. The major QAS resistance pathway involves the QacR dimer, which regulates efflux pump expression. A plausible approach to address this issue is to structurally modify the CPC structure by adding other biologically active functional groups. Here, a series of QAS based on pyridine-4-aldoxime were synthesized, characterized, and tested for antimicrobial activity in vitro. Although we obtained several potent antiviral candidates, these candidates had lower antibacterial activity than CPC and were not toxic to human cell lines. We found that the addition of an oxime group to the pyridine backbone resulted in derivatives with large topological polar surfaces and with unfavorable cLog P values. Investigation of the antibacterial mode of action, involving the cell membrane, revealed altered cell morphologies in terms of corrugated and/or disrupted surface, while 87% of the cells studied exhibited a permeabilized membrane after 3 h of treatment at 4 × minimum inhibitory concentration (MIC). Molecular dynamic (MD) simulations of the interaction of QacR with a representative candidate showed rapid dimer disruption, whereas this was not observed for QacR and QacR bound to the structural analog CPC. This might explain the lower bioactivity of our compounds, as they are likely to cause premature expression of efflux pumps and thus activation of resistance.

Synthesis and Biological Evaluation of 3-Amidoquinuclidine Quaternary Ammonium Compounds as New Soft Antibacterial Agents

“…As we previously reported, the presence of polar groups in the QAC structures can significantly alter the antibacterial activity [ 18 ]. When comparing the structures of the soft QAC series, two main structural features should be considered.…”

“…This was observed in our previous study with a structural analog of CPC differing only in the presence of an oxime group on the heterocyclic pyridinium core. The resulting QACs were practically inactive due to the strong negative influence of the polar oxime group on the otherwise highly bioactive structure of CPC [ 18 ].…”

“…Recently, our group has shown that the addition of a polar oxime group to the heterocyclic core structure of pyridine-derived QACs impairs antimicrobial activity compared to the alkyl analog cetylpyridinium chloride (CPC) [ 18 ]. However, to our knowledge, there are no reports on how the addition of a polar group, especially a polar group on the cyclic core of QACs scaffolds, affects biological activity.…”

Further Study of the Polar Group’s Influence on the Antibacterial Activity of the 3-Substituted Quinuclidine Salts with Long Alkyl Chains

“…The degradation products of soft QACs are nontoxic and therefore do not pose a threat to ecosystems, making them a good alternative to conventional QACs. However, some limitations related to the structure–activity relationship of soft QACs remain as obstacles for further study [ 24 , 25 ].…”