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The lack of new antibiotics and the rapidly rising number of pathogens resistant to antibiotics pose a serious problem to mankind. In bacteria, the cell membrane provides the first line of defence to antibiotics by preventing them from reaching their molecular target. To overcome this entrance barrier, it has been suggested [1] that small Gold-Nanoparticles (AuNP) could possibly function as drug delivery systems for antibiotic ligands. Using actinonin-based ligands, we provide here proof-of-principle of AuNP functionalisation, the capability to bind and inhibit the target protein of the ligand, and the possibility to selectively release the antimicrobial payload. To this end, we successfully synthesised AuNP coated with thio-functionalised actinonin and a derivative. Interactions between 15 N-enriched His-peptide deformylase 1-147 from E. coli (His-ecPDF 1-147) and compound-coated AuNP were investigated via 2D 1 H- 15 N-HSQC NMR spectra proving the direct binding to His-ecPDF 1-147. More importantly by adding dithiothreitol (DTT), we show that the derivative is successfully released from AuNPs while still bound to His-ecPDF 1-147. Our findings indicate that AuNP-conjugated ligands can address and bind intracellular target proteins. The system introduced here presents a new delivery platform for antibiotics and allows for the easy optimisation of ligand coated AuNPs., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Antimicrobial resistance (AMR) is a rapidly spreading global health problem, and approximately five million deaths associated with AMR pathogens were identified prior to the COVID-19 pandemic. Pseudomonas aeruginosa has developed increasing AMR, and in patients with cystic fibrosis (CF) colonized by this bacterium, rare phenotypes have emerged that complicate the diagnosis and treatment of the hosts, in addition to multiple associated "epidemic strains" with high morbidities and mortalities. The conjugation of aptamers with fluorochromes or nanostructures has allowed the design of new identification strategies for Pseudomonas aeruginosa with detection limits of up to 1 cell ⋅ mL -1 , and the synergy of aptamers with antibiotics, antimicrobial peptides and nanostructures has exhibited promising therapeutic qualities. Some selected aptamers against this bacterium have shown intrinsic antimicrobial activity. However, these aptamers have been poorly evaluated in clinical isolates and have shown decreased interactions for CF isolates, demonstrating, in these cases, uncommon phenotypes resulting from the selective qualities of this disease as well as the great adaptive capacity of the pathogen. Therefore, finding an aptamer or set of aptamers that have the ability to recognize strange phenotypes of this bacillus is crucial in the battle against AMR., (© 2023 Wiley-VCH GmbH.)

Conjugated oligoelectrolytes (COEs) are an emerging class of amphiphilic antimicrobial compounds with a modular molecular framework suitable for simple chemical derivatization. Here, a series of COE derivatives with a stilbene-conjugated segment and triphenylphosphonium (TPP) pendant groups was designed and synthesized to understand how lipophilic cationic groups impact antimicrobial activity. In vitro evaluations against ESKAPE pathogens showed broad-spectrum activity towards multi-drug resistant (MDR) bacteria and mycobacteria, with TPP groups enhancing antimicrobial activity towards clinically relevant Gram-negative strains compared to their ammonium analogues. We studied the interactions of DM6P, the most active TPP-COE compound, with various membrane assays. Treatment of bacterial cells with DM6P showed enhanced permeability of cell membranes without inducing the development of significant bacterial resistance. Moreover, DM6P eliminated 99.99 % of methicillin-resistant Staphyloccocus aureus (MRSA) in an in vivo wound model. These results represent a promising chemical strategy for increasing the activity spectrum of membrane-active COE antibiotics to tackle challenging drug-resistant targets., (© 2023 Wiley-VCH GmbH.)

Drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), pose a serious threat to human life. Therefore, there is urgent need to develop antibiotics with new chemical structures and antibacterial mechanisms, especially those that elicit little drug resistance after long-term use. Herein we synthesized three novel ruthenium complexes (Ru1-Ru3) containing the enaminone structures for the first time. At a concentration of 5 μM, Ru1-Ru3 can lead to a CFU reduction of about 5 log units towards S. aureus and MRSA. Interestingly, Ru3 displayed rapid bactericidal effects and could decrease the CFU numbers of both pathogens by 5 log units within 40 min. The control compounds (Ru4 and Ru5) without the enaminone structures displayed very poor antibacterial activity under the same conditions. Moreover, S. aureus did not show apparent drug resistance towards Ru3 after 20 passages incubation with a sublethal concentration. These results highlight the critical role of enaminone structures for antibacterial applications., (© 2023 Wiley-VCH GmbH.)

The research and development of a new antimicrobial drug using a target-based approach raises the question of whether any resulting hits will also show activity against the homologous target in other closely related organisms. While an assessment of the similarities of the predicted interactions between the identified inhibitor and the various targets is an obvious first step in answering this question, no clear and consistent framework has been proposed for how this should be done. Here we developed Multifaceted Target Specificity Analysis (MTSA) and applied it to type III pantothenate kinase (PanK III ) - an essential enzyme required for coenzyme A biosynthesis in a wide range of pathogenic bacteria - as a case study to establish if targeting a specific organism's PanK III would lead to a narrow- or broad-spectrum agent. We propose that MTSA is a useful tool and aid for directing new target-based antimicrobial drug development initiatives., (© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

A series of new 5-aryl-2,2'-bipyridines and their (polyfluoro)salicylate complexes of Cu(II), Co(II) and Mn(II) were synthesized. Their antimicrobial activity was evaluated in vitro against six strains of Trichophytons, E. floccosum, M. canis, C. ablicans and Gram-negative bacteria N. gonorrhoeae. Among azo-ligands, Ph-bipy and Tol-bipy showed promising antifungal activity (minimum inhibitory concentration (MIC)<0.8-27 μM). Their antifungal action was found can be realized via binding Fe(III) ions. Tol-bipy suppressed growth of Gram-positive bacteria S. aureus, S. aureus MRSA and their monospecies biofilms (MIC 6-16 μM). Using molecular docking, the anti-staphylococcal action mechanism based on the inhibition of S. aureus DNA gyrase GyrB was proposed for the lead compounds. Among metal complexes, Cu(II) and Mn(II) complexes based on tetrafluorosalicylic acid and Tol-bipy or Ph-bipy had the high antifungal activity (MIC<0.24-32 μM). Mn(SalF 4 -2H) 2 (Tol-bipy) 2 ] suppressed the growth of seven Candida strains at MIC 12-24 μM. [Cu(Sal-2H)(Ph-bipy)] and [Cu(SalF 3 -2H)(Ph-bipy) 2 ] showed the promising anti-gonorrhoeae activity (MIC 4.2-5.2 μM). (Cu(SalF n -2H)(Tol-bipy) 2 ], [Cu(SalF 4 -2H)(Ph-bipy) 2 ] and [Cu(SalF 3 -2H)(Ph-bipy) 2 ]) were found active against the bacteria of S. aureus, S. aureus MRSA and their biofilms (MIC 2.4-41.4 μM). The most active compounds were tested for toxicity in vitro against human embryonic kidney (HEK-293) cells and in vivo experiments with CD-1 mice., (© 2021 Wiley-VCH GmbH.)

We report a novel family of natural lipoglycopeptides produced by Streptomyces sp. INA-Ac-5812. Two major components of the mixture, named gausemycins A and B, were isolated, and their structures were elucidated. The compounds are cyclic peptides with a unique peptide core and several remarkable structural features, including unusual positions of d-amino acids, lack of the Ca 2+ -binding Asp-X-Asp-Gly (DXDG) motif, tyrosine glycosylation with arabinose, presence of 2-amino-4-hydroxy-4-phenylbutyric acid (Ahpb) and chlorinated kynurenine (ClKyn), and N-acylation of the ornithine side chain. Gausemycins have pronounced activity against Gram-positive bacteria. Mechanistic studies highlight significant differences compared to known glyco- and lipopeptides. Gausemycins exhibit only slight Ca 2+ -dependence of activity and induce no pore formation at low concentrations. Moreover, there is no detectable accumulation of cell wall biosynthesis precursors under treatment with gausemycins., (© 2021 Wiley-VCH GmbH.)