Pharmacodynamic Functions of Synthetic Derivatives for Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis

Abstract

Drug resistant bacteria have emerged, so robust methods are needed to evaluate combined activities of known antibiotics as well as new synthetic compounds as novel antimicrobial agents to treatment efficacy in severe bacterial infections. Marine natural products (MNPs) have become new strong leads in the drug discovery endeavor and an effective alternative to control infections. Herein, we report the bioassay guided fractionation of marine extracts from the sponges Lendenfeldia, Ircinia, and Dysidea that led us to identify novel compounds with antimicrobial properties. Chemical synthesis of predicted compounds and their analogs has confirmed that the proposed structures may encode novel chemical structures with promising antimicrobial activity against the medically important pathogens. Several of the synthetic analogs exhibited potent and broad spectrum in vitro antibacterial activity, especially against the Methicillin-resistant Staphylococcus aureus (MRSA) (MICs to 12.5 μM), Mycobacterium tuberculosis (MICs to 0.02 μM), uropathogenic Escherichia coli (MIC o 6.2 μM), and Pseudomonas aeruginosa (MIC to 3.1 μM). Checkerboard assay (CA) and time-kill studies (TKS) experiments analyzed with the a pharmacodynamic model, have potentials for in vitro evaluation of new and existing antimicrobials. In this study, CA and TKS were used to identify the potential benefits of an antibiotic combination (i.e., synthetic compounds, vancomycin, and rifampicin) for the treatment of MRSA and M. tuberculosis infections. CA experiments indicated that the association of compounds 1a and 2a with vancomycin and compound 3 with rifampicin combination have a synergistic effect against a MRSA and M. tuberculosis infections, respectively. Furthermore, the analysis of TKS uncovered bactericidal and time-dependent properties of the synthetic compounds that may be due to variations in hydrophobicity and mechanisms of action of the molecules tested. The results of cross-referencing antimicrobial activity, and toxicity, CA, and Time-Kill experiments establish that these synthetic compounds are promising potential leads, with a favorable therapeutic index for antimicrobial drug development.

Identification of Bioactive Compounds from Marine Natural Products and Exploration of Structure-Activity Relationships (SAR)

“…The SAR was investigated through commercially available compounds of three groups of molecules, namely the tertiary amines, benzyl substituted amines [ 29 ], and the ascididemin structural motifs. To investigate the number of carbons in the linear chains, commercially available amines compounds with structures similar to synthesised compounds 3 and 13 [ 29 ] ( Figure 3 ), such as triethylamine, tributylamine and trihexylamine were screened; in addition, the primary and secondary amines hexylamine, dihexylamine and dioctylamine were screened. Biological activities of commercial compounds are based on the molecular weight of the proposed structures.…”

“…Further structures related to 1a, 1b and 2a [ 29 ] and the sequence of benzylamine, dibenzylamine, tribenzylamine, were investigated ( Figure 4 ). Observations from this experiment correlate with the increased substitution leading to increased bioactivity against P. aeruginosa .…”

“…Natural product extracts were provided by the Australian Institute of Marine Science (AIMS), Townsville, Australia as part of the AIMS Bioresources Library [28], via the Queensland Compound Library, Brisbane, Australia [29], (now called Compounds Australia [30]). Crude extracts had been partially fractionated by AIMS/ QCL to generate a library of 1434 samples, supplied in DMSO (100%) solution and stored at −80 • C. Original concentrations as provided were 5 mg mL −1 .…”

“…Following on from these studies, we decided to screen commercially available compounds, with structural similarity to the amine scaffolds we identified, synthesised [ 29 ] and ascididemin-like compounds. Thus, we found these molecules to be an interesting potential structure for further development, focusing on increasing antimicrobial potency by investigating the structure—activity relationship (SAR).…”

Rapid Monitoring of Vancomycin Concentration in Serum Using Europium (III) Chelate Nanoparticle-Based Lateral Flow Immunoassay

“…In recent years, it has spread around the world at an alarming rate ( Yagnik et al, 2021 ). MRSA has a broad spectrum of drug resistance to frequently-used β-lactam and cephalosporin antibiotics, as well as to aminoglycosides, macrolides, tetracyclines, fluoroquinolones, sulfonamides, and rifampicin with varying degrees, which makes its clinical management very challenging ( Dinarvand et al, 2020 ). Fortunately, MRSA remains susceptible to vancomycin (VAN), one of the strongest antibiotics as yet known, which is recommended intravenously as a first-line treatment for complicated infections caused by MRSA ( Holubar et al, 2020 ).…”