Small-Molecule Suppression of β-Lactam Resistance in Multidrug-Resistant Gram-Negative Pathogens

Abstract

Recent efforts toward combating antibiotic resistance in bacteria have focused on Gram-positive bacteria; however, multidrug-resistant Gram-negative bacteria pose a significant risk to public health. An orthogonal approach to the development of new antibiotics is to develop adjuvant compounds that enhance the susceptibility of drug-resistant strains of bacteria to currently approved antibiotics. This paper describes the synthesis and biological activity of a library of aryl amide 2-aminoimidazoles based on a lead structure from an initial screen. A small molecule was identified from this library that is capable of lowering the minimum inhibitory concentration of β-lactam antibiotics by up to 64-fold.

Structure of the Francisella response regulator QseB receiver domain, and characterization of QseB inhibition by antibiofilm 2‐aminoimidazole‐based compounds

“…From a library of 2‐AIs, the compound AGL‐600 (Fig. A) was initially selected to study, as it demonstrates significant activity in cellular studies (Brackett et al ., ). To characterize potential interactions between 2‐AIs and QseB, it was first necessary to establish that AGL‐600 does indeed bind to QseB.…”

“…A cell‐permeable family of 2‐aminoimidazole (2‐AI) derivatives are known to interact with response regulators (Thompson et al ., ). 2‐AIs have been widely shown to inhibit and disperse biofilms and also to work synergistically with traditional antibiotics to re‐sensitize multidrug‐resistant bacteria (Richards et al ., ; Rogers and Melander, ; Ballard et al ., ; Brackett et al ., ). The specific mechanism by which 2‐AIs interact with response regulators remains mostly unknown.…”

Second generation modifiers of colistin resistance show enhanced activity and lower inherent toxicity

“…5 The mechanistic basis of colistin resistance is thought to occur predominantly through modification of lipid A 6 ; however, the two-component system (TCS) signaling that drives these modifications has recently been shown to activate additional mechanisms that are also required for resistance. 7 Our group has been focused on combating the inevitable development of antibiotic resistant bacteria by developing compounds capable of disrupting the mechanisms through which these organisms express resistance 8–12 . We recently established that the 2-aminoimidazole (2-AI) compound 1 is capable of reversing colistin resistance in multiple primary clinical isolates of two of the four Gram-negative ESKAPE pathogens: K. pneumoniae , and A. baumannii .…”

Combinations of Carbapenem with Fluoroquinolones or 1,3,4 -Oxadiazole-2 -Thione Derivatives as New Broad Spectrum Bactericidal Antibiotics for Ophthalmic Preparation

“…The FT-IR spectrum of compound, show the υ cm-1 (KBr disc): 3221 for N-H stretching, 2985&2729 for aliphatic C-H stretching aromatic & aliphatic, 1724 for C = O group of ester, 1612 for N-H bending. 1 H-NMR (δ, ppm) (DMSO-d6), show the following signals: 1.15-1.43 (t, 3H) CH 3 , 2.32-2.62 (q, 2H) CH 2 , 7.45-7.82 (dd, 4H) 5.41(m, 3H) for N-H, 8.08-8.88 (dd, 4H) for para substituted aromatic ring. D 2 O was added to identify the N-H proton, after addition and mix the NMR tube and measure again for the sample, new peak 3.76 ppm strong peak for HOD, give a good evidence for proton exchange.…”

“…Recent efforts towards combating antibiotic resistance in bacteria have focused on on G +ve bacteria; however, multidrug-resistant G -ve bacteria pose a significant risk to public health. An orthogonal approach to the development of new antibiotics is to develop adjuvant compound that enhance the susceptibility of drug -resistant strains of bacteria to currently approved antibiotic [1].…”