An official website of the United States government
Abstract Cationic biocides play a crucial role in the disinfection of domestic and healthcare surfaces. Due to the rise of bacterial resistance towards common cationic disinfectants like quaternary ammonium compounds (QACs), the development of novel actives is necessary for effective infection prevention and control. Toward this end, a series of 15 chimeric biscationic amphiphilic compounds, bearing both ammonium and phosphonium residues, were prepared to probe the structure and efficacy of mixed cationic ammonium‐phosphonium structures. Compounds were obtained in two steps and good yields, with straightforward and chromatography‐free purifications. Antibacterial activity evaluation of these compounds against a panel of seven bacterial strains, including two MRSA strains as well as opportunistic pathogenA. baumannii, were encouraging, as low micromolar inhibitory activity was observed for multiple structures. Alkyl chain length on the ammonium group was, as expected, a major determinant of bioactivity. In addition, high therapeutic indexes (up to 125‐fold) for triphenyl phosphonium‐bearing amphiphiles were observed when comparing antimicrobial activity to mammalian cell lysis activity.
more »
« less
Double BAC and Triple BAC: A Systematic Analysis of the Disinfectant Properties of Multicationic Derivatives of Benzalkonium Chloride (BAC)
Abstract Over the past decades, the shortcomings of established quaternary ammonium disinfectants have become increasingly clear. Although benzalkonium chloride (BAC) has enjoyed nearly a century of significantly protecting human health through surgical preparation, home use, and industrial applications, increasing levels of bacterial resistance have rendered it decreasingly effective. In light of more recent efforts that have informed us that multicationic amphiphilic disinfectants show both higher activity as well as diminished susceptibility to resistance, we embarked on the preparation of 27 multicationic QACs in an attempt to clearly document structure‐activity relationships of next‐generation BAC structures. Select biscationic BAC derivatives demonstrate single‐digit micromolar activity against all seven bacteria tested and MIC values of 2‐ to 32‐fold better than BAC. Particularly notable is the improvement against the more concerning bacteria likeAcinetobacter baumanniiandPseudomonas aeruginosa, which pose a modern threat to legacy disinfectants like BAC. With simple synthetic paths, consistently high yields (averaging ∼80 %), and strong biological activity, potent structures with clear SAR trends and strong therapeutic indices have been established.
more »
« less
- PAR ID:
- 10401469
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemMedChem
- Volume:
- 18
- Issue:
- 10
- ISSN:
- 1860-7179
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Abstract Reaction of Tl(OTf) with 2 equiv of bis(diisopropylamino)cyclopropenylidene (BAC) in THF results in formation of [Tl(BAC)2(OTf)] (1) in moderate yields. Subsequent reaction of1with [K][H2‐9‐BBN] ([H2‐9‐BBN]− = dihydrido 9‐boratabicyclo[3.3.1]nonane) in THF results in formation of [Tl(BAC)(μ‐H2‐9‐BBN)]2(3), also in moderate yield. Complex3is the first reported thallium borohydride. We attribute its thermal stability to the strong donor ability of the BAC co‐ligand. Both1and3exhibit trigonal pyramidal geometries about Tl+in the solid‐state, indicative of the presence of stereochemically active lone pairs. The hydride environment in3is calculated to exhibit a 3.9 ppm downfield shift attributed to spin‐orbit effects from the adjacent Tl center.more » « less
-
Abstract The emergence and spread of antimicrobial resistance highlights the urgent need for new antibiotics. Organoarsenicals have been used as antimicrobials since Paul Ehrlich’s salvarsan. Recently a soil bacterium was shown to produce the organoarsenical arsinothricin. We demonstrate that arsinothricin, a non-proteinogenic analog of glutamate that inhibits glutamine synthetase, is an effective broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria, suggesting that bacteria have evolved the ability to utilize the pervasive environmental toxic metalloid arsenic to produce a potent antimicrobial. With every new antibiotic, resistance inevitably arises. ThearsN1gene, widely distributed in bacterial arsenic resistance (ars) operons, selectively confers resistance to arsinothricin by acetylation of the α-amino group. Crystal structures of ArsN1N-acetyltransferase, with or without arsinothricin, shed light on the mechanism of its substrate selectivity. These findings have the potential for development of a new class of organoarsenical antimicrobials and ArsN1 inhibitors.more » « less
-
Invasive fungal infections are increasing worldwide due to an expanding number of immunocompromised patients as well as an increase in drug-resistant fungi. While fungal resistance has increased, this resistance has not been accompanied by the development of new antifungals. A common class of antifungal agents that are prescribed are the azoles, which contain either a triazole or an imidazole group. Unfortunately, current azoles, like fluconazole, have been shown to be less effective with the increase in resistant fungal pathogens. Therefore, the development of novel azole antifungal compounds is of urgent need. The objective of this research was to synthesize triazole-containing small molecules with potent antifungal activity. The scaffold of the synthesized compounds contains a triazole moiety and was synthesized via a copper-catalyzed azide-alkyne click reaction (CuAAC) between the appropriate alkyne and azide intermediates. The minimum inhibitory concentrations of these compounds were determined using standard broth microdilution assays against opportunistic bacteria and fungi associated with life-threatening invasive fungal infections. Although the synthesized compounds possessed no antimicrobial activity, these results can be used to further the long-term goal of developing and optimizing lead compounds with potentin vitroantifungal activity.more » « less
-
Abstract The language contact between Basque and Spanish in the Basque Autonomous Community (BAC) gives rise to the production of specific linguistic features such as non-standard gender agreement (N-SGA). N-SGA in BAC Spanish has been traditionally attributed to elder Basque native speakers without much access to education, but this affirmation is not based on any empirical study. In addition, although several scholars have explored N-SGA in other language contact situations, there is no agreement on the linguistic factors that favor this production. Taking this knowledge gap as the point of departure, the present study explores 73 individual sociolinguistic interviews by a diverse population from the BAC in order to delimit (i) the community that produces N-SGA and (ii) the linguistic factors that condition it. Results follow Basterretxea Santiso’s (2022, “A triangulation study on gender agreement in Spanish by native Basque speakers.”Revista Española de Lingüística (RSEL)52(1): 7–37) suggestion that N-SGA in BAC Spanish is present across generations: it is a well-established feature present in BAC Spanish as a result of language contact. Results also support the existence of a local gender agreement system that depends on the gender of the controller, inflectional form, number, distance, and whether the target is a clitic or adjective.more » « less
