5-Alkyloxytryptamines are membrane-targeting, broad-spectrum antibiotics

Abstract

Antibiotic adjuvant therapy represents an exciting opportunity to enhance the activity of clinical antibiotics by co-dosing with a secondary small molecule. Successful adjuvants decrease the concentration of antibiotics used to defeat bacteria, increase activity (in some cases introducing activity against organisms that are drug resistant), and reduce the frequency at which drug-resistant bacteria emerge. We report that 5-alkyloxytryptamines are a new class of broad-spectrum antibacterial agents with exciting activity as antibiotic adjuvants. We synthesized 5-alkyloxytryptamine analogs and found that an alkyl chain length of 6–12 carbons and a primary ammonium group are necessary for the antibacterial activity of the compounds, and an alkyl chain length of 6–10 carbons increased the membrane permeability of gram-positive and gram-negative bacteria. Although several of the most potent analogs also have activity against the membranes of human embryonic kidney cells, we demonstrate that below the minimum inhibitory concentration (MIC)—where mammalian cell toxicity is low—these compounds may be successfully used as adjuvants for chloramphenicol, tetracycline, ciprofloxacin, and rifampicin against clinical strains of Salmonella typhimurium, Acinetobacter baumannii and Staphylococcus aureus, reducing MIC values by as much as several logs.

The Mycobacterial Membrane: A Novel Target Space for Anti-tubercular Drugs

“…Despite several appealing properties (rapid killing, low immunogenicity, uptake by macrophages, immunomodulatory properties) which render AMPs highly attractive as antimycobacterial candidates, their clinical advancement has been hampered by stability and pharmacokinetic issues arising from their peptidic character (Arranz-Trullén et al, 2017 ). Non-peptidic membrane targeting small molecules would arguably overcome these limitations and several such entities have been investigated against Gram-positive and Gram-negative bacteria with promising outcomes (Vooturi et al, 2009 , 2011 ; Eun et al, 2012 ; Zou et al, 2013 ; Hurley et al, 2015 ; Faulkner et al, 2016 ; Koh et al, 2016a ; Wang et al, 2016 ; Shuimu et al, 2017 ; Su et al, 2017 ). In comparison, the concept of damaging the structure of mycobacterial membrane bilayer as a therapeutic strategy has received less attention.…”

Novel Oleanolic Acid-Tryptamine and -Fluorotryptamine Amides: From Adaptogens to Agents Targeting In Vitro Cell Apoptosis

“…The tryptamine scaffold is regarded as a structure of priority importance due to its broad applications in the design of medicinal agents [ 11 ]. Tryptamine analogues have been reported to display pharmacological activity, such as anti-migraine [ 12 ], antibacterial [ 13 , 14 ] and antitumor effects [ 15 , 16 , 17 ]. Tryptamine itself has been found not to reduce cell viability [ 16 ].…”