Biofilms are linked to resistance development in the ESKAPE pathogens. This perspective summarizes several strategies for affecting iron homeostasis that have been implicated in biofilm inhibition.
The 1,2,3‐triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX‐809 and VX‐770, prominent amide‐containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX‐809, displayed markedly reduced efficacy in F508del‐CFTR correction in cellular TECC assays in comparison to VX‐809. Surprisingly, triazole analogues derived from potentiator VX‐770 displayed no potentiation of F508del, G551D, or WT‐CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT‐CFTR similarly to VX‐770. The efficacy of 60 in the cell‐free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX‐770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3‐triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3‐triazole as an amide bioisostere.
Acinetobacter baumannii is classified
as a highest threat pathogen, urgently necessitating novel antimicrobials
that evade resistance to combat its spread. Quaternary ammonium compounds
(QACs) have afforded a valuable first line of defense against antimicrobial
resistant pathogens as broad-spectrum amphiphilic disinfectant molecules.
However, a paucity of innovation in this space has driven the emergence
of QAC resistance. Through this work, we sought to identify next-generation
disinfectant molecules with efficacy against highly resistant A. baumannii clinical isolates. We selected 12 best-in-class
molecules from our previous investigations of quaternary ammonium
and quaternary phosphonium compounds (QPCs) to test against a panel
of 35 resistant A. baumannii clinical
isolates. The results highlighted the efficacy of our next-generation
compounds over leading commercial QACs, with our best-in-class QAC
(2Pyr-11,11) and QPC (P6P-10,10) displaying improved activities with
a few exceptions. Furthermore, we elucidated a correlation between
colistin resistance and QAC resistance, wherein the only pan-resistant
isolate of the panel, also harboring colistin resistance, exhibited
resistance to all tested QACs. Notably, P6P-10,10 maintained efficacy
against this strain with an IC90 of 3 μM. In addition,
P6P-10,10 displayed minimum biofilm eradication concentrations as
low as 32 μM against extensively drug resistant clinical isolates.
Lastly, examining the development of disinfectant resistance and cross-resistance,
we generated QAC-resistant A. baumannii mutants and observed the development of QAC cross-resistance. In
contrast, neither disinfectant resistance nor cross-resistance was
observed in A. baumannii under P6P-10,10
treatment. Taken together, the results of this work illustrate the
need for novel disinfectant compounds to treat resistant pathogens,
such as A. baumannii, and underscore
the promise of QPCs, such as P6P-10,10, as viable next-generation
disinfectant molecules.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.