To accurately predict binding of inhibitors to the FtsZ cell division protein of the antibiotic-resistance Staphilococcus aureus pathogen, evolutionary library docking, ligand-efficiency predictions and rank consensus docking strategies have been sequentially applied. Starting from the crystallographic FtsZ bound model of the PC190723 reference ligand, fragments were derived to generate children molecules fitting low docking-scores with low molecular sizes and hydrophobicities using the DataWarrior Build Evolutionary Library. PC190723 fragment children molecules combined with toxicity filters, and consensus ranks with ligand efficiencies and AutoDockVina docking, identified new benzamide and non-benzamide chemotypes with nanomolar docking-scores and improved specificities to continue with anti-FtsZ ligand investigations 

/pdf/evolutionary-docking-targeting-bacterial-ftsz-n7qerlge.pdf

Evolutionary-docking targeting bacterial FtsZ

Drug-spaces of nine crystallographic protein / ligand models have been comparatively explored by including Toxicity Risk assessment during computational co-evolution. Tens of thousands children were randomly generated from parent ligands and iteratively selected for higher affinities, increased specificities and low Toxicity Risk using DataWarrior / Build Evolutionary Library algorithms, mimicking natural evolution. Only a few hours of co-evolution increased ~ 2-fold the numbers of non-toxic children. Top-leads predicted drug-like properties, nanoMolar affinities (confirmed by AutoDockVina), higher specificities, absence of known toxicities, and similar docking to their initial binding cavities. Tables were provided with multi-threshold-adjustable filters for alternative in silico explorations of this new "co-evolutionary docking" tool. 

Exploring non-toxic co-evolutionary docking

Many approaches are being pursued to address the major global health challenge posed by the increasing resistance of pathogenic bacteria to antibacterial agents. One of the promising approaches being investigated includes the design and development of multiple action-based small-molecule antibacterials. Aspects of this broad area have been reviewed previously, and recent developments are addressed in this update review covering the literature mainly over the past three years. Considerations encompassing drug combinations, single-molecule hybrids and prodrugs are summarised in regard to the intentional design and development of multiple-action agents with a focus on potential triple or greater activities in bacteria. The hope for such single agents or combinations of single agents is that resistance development will be significantly hindered, and they may be useful in tackling bacterial disease caused by both resistant and non-resistant bacteria.

/pdf/an-update-review-of-approaches-to-multiple-action-based-1yjfkrdq.pdf

An Update Review of Approaches to Multiple Action-Based Antibacterials

BACKGROUND: Myrtillin is a pigment found abundantly in a variety of fruits and vegetables. As an anthocyanin compound, myrtillin exhibits antioxidant properties that can potentially counteract oxidative damage. OBJECTIVE: In this study, we focus on investigating the protective effects of myrtillin on Caenorhabditis elegans against pathogen-induced oxidative damage. Specifically, we explore the impact of myrtillin on the lifespan of C . elegans when exposed to different pathogens, namely Staphylococcus aureus , Enterococcus faecalis , Klebsiella pneumoniae , and Proteus mirabilis . MATERIALS AND METHODS: To conduct our experiments, C . elegans were administered varying concentrations of myrtillin and subsequently infected with each of the aforementioned pathogens. The nematodes’ lifespan was carefully monitored under these conditions. We also docked the three-dimensional structure of myrtillin to the crystal structure of different bacterial proteins. We visualized the crystal-docked structures with the lowest binding energy. RESULTS: Our findings revealed a significant increase in the lifespan of C. elegans when exposed to S . aureus , E . faecalis , K . pneumoniae , and P . mirabilis ( P ≤ 0.05). It is worth noting that the effectiveness of myrtillin in extending lifespan varied among these pathogens. Notably, we observed that myrtillin exhibited low binding energies toward specific bacterial proteins, namely filamenting temperature-sensitive mutant Z of S. aureus and NAD + -dependent DNA ligase of E . faecalis . These interactions involved a combination of hydrogen bonds and hydrophobic interactions. In addition, myrtillin demonstrated the lowest binding energy with SHV-2 of K . pneumoniae and amidohydrolase of P . mirabilis , characterized by a higher number of hydrogen bonds. CONCLUSION: Based on our observations, we speculate that myrtillin possesses an additional protective mechanism against a range of pathogens, ultimately leading to an extended lifespan in C . elegans . This suggests the potential of myrtillin as a beneficial compound with diverse protective properties against various pathogens. Further research is required to elucidate the precise mechanisms underlying myrtillin’s effects and its potential application in promoting health and longevity. 

Myrtillin Prolongs Lifespan and Enhances Tolerance against Pathogenic Infections in Caenorhabditis elegans

MreB is a cytoskeleton protein present in rod-shaped bacteria that is both essential for bacterial cell division and highly conserved. Because most Gram (-) bacteria require MreB for cell division, chromosome segregation, cell wall morphogenesis, and cell polarity, it is an attractive target for antibacterial drug discovery. As MreB modulation is not associated with the activity of antibiotics in clinical use, acquired resistance to MreB inhibitors is also unlikely. Compounds, such as A22 and CBR-4830, are known to disrupt MreB function by inhibition of ATPase activity. However, the toxicity of these compounds has hindered efforts to assess the in vivo efficacy of these MreB inhibitors. The present study further examines the structure-activity of analogs related to CBR-4830 as it relates to relative antibiotic activity and improved drug properties. These data reveal that certain analogs have enhanced antibiotic activity. In addition, we evaluated several representative analogs (9, 10, 14, 26, and 31) for their abilities to target purified E. coli MreB (EcMreB) and inhibit its ATPase activity. Except for 14, all these analogs were more potent than CBR-4830 as inhibitors of the ATPase activity of EcMreB with corresponding IC50 values ranging from 6 ± 2 to 29 ± 9 μM. 

Novel MreB inhibitors with antibacterial activity against Gram (-) bacteria

The emergence of multi-drug-resistant Gram-negative pathogens highlights an urgent clinical need to explore and develop new antibiotics with novel antibacterial targets. MreB is a promising antibacterial target that functions as an essential elongasome protein in most Gram-negative bacterial rods. Here, we describe a third-generation MreB inhibitor (TXH11106) with enhanced bactericidal activity versus the Gram-negative pathogens Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa compared to the first- and second-generation compounds A22 and CBR-4830, respectively. Large inocula of these four pathogens are associated with a low frequency of resistance (FOR) to TXH11106. The enhanced bactericidal activity of TXH11106 relative to A22 and CBR-4830 correlates with a correspondingly enhanced capacity to inhibit E. coli MreB ATPase activity via a noncompetitive mechanism. Morphological changes induced by TXH11106 in E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa provide further evidence supporting MreB as the bactericidal target of the compound. Taken together, our results highlight the potential of TXH11106 as an MreB inhibitor with activity against a broad spectrum of Gram-negative bacterial pathogens of acute clinical importance.

/pdf/txh11106-a-third-generation-mreb-inhibitor-with-enhanced-3vjuvzeo.pdf

TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens

Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant (MDR) bacterial pathogen of acute clinical significance. Resistance to current standard-of-care antibiotics, such as vancomycin and linezolid, among nosocomial and community-acquired MRSA clinical isolates is on the rise. This threat to global public health highlights the need to develop new antibiotics for the treatment of MRSA infections. Here, we describe a new benzamide FtsZ inhibitor (TXH9179) with superior antistaphylococcal activity relative to earlier-generation benzamides like PC190723 and TXA707. TXH9179 was found to be 4-fold more potent than TXA707 against a library of 55 methicillin-sensitive S. aureus (MSSA) and MRSA clinical isolates, including MRSA isolates resistant to vancomycin and linezolid. TXH9179 was also associated with a lower frequency of resistance relative to TXA707 in all but one of the MSSA and MRSA isolates examined, with the observed resistance being due to mutations in the ftsZ gene. TXH9179 induced changes in MRSA cell morphology, cell division, and FtsZ localization are fully consistent with its actions as a FtsZ inhibitor. Crystallographic studies demonstrate the direct interaction of TXH9179 with S. aureus FtsZ (SaFtsZ), while delineating the key molecular contacts that drive complex formation. TXH9179 was not associated with any mammalian cytotoxicity, even at a concentration 10-fold greater than that producing antistaphylococcal activity. In serum, the carboxamide prodrug of TXH9179 (TXH1033) is rapidly hydrolyzed to TXH9179 by serum acetylcholinesterases. Significantly, both intravenously and orally administered TXH1033 exhibited enhanced in vivo efficacy relative to the carboxamide prodrug of TXA707 (TXA709) in treating a mouse model of systemic (peritonitis) MRSA infection. Viewed as a whole, our results highlight TXH9179 as a promising new benzamide FtsZ inhibitor worthy of further development.

Structural and Antibacterial Characterization of a New Benzamide FtsZ Inhibitor with Superior Bactericidal Activity and In Vivo Efficacy Against Multidrug-Resistant Staphylococcus aureus.

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TXH11106: A Third-Generation MreB Inhibitor with Enhanced Activity against a Broad Range of Gram-Negative Bacterial Pathogens

Structural and Antibacterial Characterization of a New Benzamide FtsZ Inhibitor with Superior Bactericidal Activity and In Vivo Efficacy Against Multidrug-Resistant Staphylococcus aureus.

Novel MreB inhibitors with antibacterial activity against Gram (-) bacteria