Second‐Generation Meridianin Analogues Inhibit the Formation of Mycobacterium smegmatis Biofilms and Sensitize Polymyxin‐Resistant Gram‐Negative Bacteria to Colistin

Abstract

Drug‐resistant bacteria are rapidly becoming a significant problem across the globe. One element that factors into this crisis is the role played by bacterial biofilms in the recalcitrance of some infections to the effects of conventional antibiotics. Bacteria within a biofilm are highly tolerant of both antibiotic treatment and host immune responses. Biofilms are implicated in many chronic infections, including tuberculosis, in which they can act as bacterial reservoirs, requiring an arduous antibiotic regimen to eradicate the infection. A separate, compounding problem is that antibiotics once seen as last‐resort drugs, such as the polymyxin colistin, are now seeing more frequent usage as resistance to front‐line drugs in Gram‐negative bacteria becomes more prevalent. The increased use of such antibiotics inevitably leads to an increased frequency of resistance. Drugs that inhibit biofilms and/or act as adjuvants to overcome resistance to existing antibiotics will potentially be an important component of future approaches to antibacterial treatment. We have previously demonstrated that analogues of the meridianin natural product family possess adjuvant and antibiofilm activities. In this study, we explore structural variation of the lead molecule from previous studies, and identify compounds showing both improved biofilm inhibition potency and synergy with colistin.

Identification and Evaluation of Brominated Carbazoles as a Novel Antibiotic Adjuvant Scaffold in MRSA

“… 18 , 19 Additionally, brominated derivatives of the kinase inhibitor meridianin D, which bears structural similarity to carbazoles, have been shown to inhibit biofilm formation in MRSA. 20 , 21 An evaluation of regulatory kinases in S. aureus suggested that the PASTA kinase Stk1 could be the molecular target of the lead carbazoles. Stk1 is a global regulator of cell-wall homeostasis and biofilm formation and has been implicated in the regulation of resistance to β-lactams and vancomycin.…”

Evaluation of small molecule kinase inhibitors as novel antimicrobial and antibiofilm agents

“…The Melander group recently reported the synthesis and evaluation of indolylpyrimidine analogs of meridianin D that potentiate colistin in Gram-negative bacteria (Huggins et al, 2018;Zeiler et al, 2020). Meridianin D (50, Figure 5), which is structurally related to the pyrazolopyridazines described above, was isolated from a marine invertebrate and has been previously reported as a kinase inhibitor (Franco et al, 1998;Giraud et al, 2011;Gompel et al, 2004).…”

“…Analog 51 displayed enhanced potentiation, lowering the colistin MIC 512-fold in both A. baumannii 4106 and K. pneumoniae B9 (Figure 5). Second-generation analogs further elaborated the structure-activity relationship and provided additional analogs (52, 53, Figure 5) with phenyl groups that showed comparable colistin potentiation as 51 in A. baumannii and K. pneumoniae (Zeiler et al, 2020). Additionally, 52 was able to lower the MIC of colistin to the resistance breakpoint at a concentration of only 5 μM, indicating that this analog has improved potency and activity of the previous lead analog, 51, which required at least 10 μM dosing to achieve similar results.…”

“…In addition to potentiating colistin in medically relevant Gram-negative bacteria, meridianin D and those analogs reported by the Melander lab were also found to disrupt biofilm formation in MRSA and M. smegmatis (Huggins et al, 2018;Zeiler et al, 2020). In their initial disclosure, the group evaluated their first-generation analogs for the ability to inhibit MRSA biofilm formation to generate an initial structure-activity relationship (Huggins et al, 2018).…”

2-Aminoimidazoles Inhibit Mycobacterium abscessus Biofilms in a Zinc-Dependent Manner

“…With the premise that agents capable of inhibiting M. abscessus biofilm formation and/or of dispersing established M. abscessus biofilms may potentiate the activity of antibiotics used in combination, our attention turned to 2-aminoimidazoles (2-AI). The decision to study 2-AIs was based upon previous studies by the Melander laboratory and others that showed that the 2-AI class of small molecules and related scaffolds (2-aminopyrimidines (2-AP), 2-aminobenzimidazoles (2-ABI), 2-aminoquinazolines and 2-AI-containing meridianin analogs) display broad-spectrum biofilm inhibition and dispersion activity against Gram-negative and Gram-positive bacteria, including Mycobacterium tuberculosis and the nontuberculous Mycobacterium species, M. smegmatis [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Importantly, some 2-AI and 2-ABI compounds demonstrated the ability to sensitize M. tuberculosis and M. smegmatis to isoniazid, rifampicin and β-lactams [ 15 , 19 , 23 , 25 ].…”