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.
Highlights
The first isolation of methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis was reported in 1882 and 1961, respectively (Enright et al, 2002; Cambau and Drancourt, 2014)
Twenty-three compounds from extracts and fractions derived from the phyla Porifera (90%), Echinodermata (5%), and Chordata (5%) inhibited of MRSA growth by greater than 50% compared to non-treated controls (Supplementary Table S1)
Cytotoxicity screens against HepG2, HEK 293, human alveolar epithelial cells (A549) and human leukemia cells (THP-1) cell lines were performed to define the cytotoxicity profile of the most active samples (Supplementary Table S2)
Summary
The first isolation of methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis was reported in 1882 and 1961, respectively (Enright et al, 2002; Cambau and Drancourt, 2014). The increasing prevalence of antibiotic resistance and lack of clinically approved treatments has made these infections a new challenge for infection control teams worldwide (Enright et al, 2002; Zaman, 2010; Diallo et al, 2018; Yang et al, 2018). This determined existing antibiotic therapies require substantial improvements in efficacy, in order to overcome severe chronic bacterial infections (Broussou et al, 2019; Dinarvand and Peter Spain, 2020). The Demospongiae, being most abundant class of Porifera, represent 83% of described species (Van Soest et al, 2012; Matobole et al, 2017) and have the largest number of bioactive compounds (El-Damhougy et al, 2017)
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