Search

The analysis of antimicrobial activity is usually MIC- and minimal bactericidal concentration (MBC)-focused, though also crucial are resistance-related parameters, e.g., the frequency of spontaneous mutant selection (FSMS), the mutant prevention concentration (MPC), and the mutant selection window (MSW). In vitro -determined MPCs, however, are sometimes variable, poorly repeatable, and not always reproducible in vivo . We propose a new approach to the in vitro determination of MSWs, along with novel parameters: MPC-D, MSW-D (for dominant mutants, i.e., selected with a high frequency, without a fitness loss), and MPC-F, MSW-F (for inferior mutants, i.e., with an impaired fitness). We also propose a new method for preparing the high-density inoculum (>10 11 CFU/mL). In this study, the MPC and MPC-D (limited by FSMS of <10 -10 ) of ciprofloxacin, linezolid, and novel benzosiloxaborole (No37) were determined for Staphylococcus aureus ATCC 29213 using the standard agar method, while the MPC-D and MPC-F were determined by the novel broth method. Regardless of the method, MSWs 10 10 of linezolid and No37 were the same. However, MSWs 10 10 of ciprofloxacin in the broth method was narrower than in the agar method. In the broth method, the 24-h incubation of ~10 10 CFU in a drug-containing broth differentiates the mutants that can dominate the cell population from those that can only be selected under exposure. We consider MPC-Ds in the agar method to be less variable and more repeatable than MPCs. Meanwhile, the broth method may decrease discrepancies between in vitro and in vivo MSWs. The proposed approaches may help establish MPC-D-related resistance-restricting therapies., Competing Interests: The authors declare no conflict of interest.

Disinfectants and antiseptics lead in reducing the number of microorganisms, including pathogenic ones, thus limiting the number of infections. In the veterinary field, disinfection prevents the transfer of pathogenic microorganisms from animals to humans and vice versa, as well as among animals. Several assays of disinfectant antimicrobial activity testing, often not standardized, without appropriate controls, and not validated, have been used and published. To unify these methods, nine European Standards (ENs) for the veterinary area have been prepared. These tests make it possible to examine whether a given disinfectant has bactericidal, fungicidal, or virucidal activity by the standard. This publication discusses ENs regarding the assessment of the above-mentioned antimicrobial activity of disinfectants used in veterinary medicine. Recent research on this topic has also been cited. According to ENs, tests are carried out using the suspension method or carriers in clean and dirty conditions. The decontamination of high-risk animal and zoonotic pathogens is also discussed. Selected publications on cattle, pig, poultry, and aquaculture farm disinfection are presented. Only valid methods of the described studies with appropriate statistical analysis can prove adequate antimicrobial activity. So far, the role of international standards in investigating the antimicrobial activity of disinfectants and antiseptics to reduce infections has been underestimated. This publication highlights gaps and irregularities in conducted research and aims to inform about existing EN standards dedicated to testing the biocidal activity of disinfectants and antiseptics intended for use in the veterinary area. [ABSTRACT FROM AUTHOR]

Despite the urgent need for new antibiotics, very few innovative antibiotics have recently entered clinics or clinical trials. To provide a constant supply of new drug candidates optimized in terms of their potential to select for resistance in natural settings, in vitro resistance-predicting studies need to be improved and scaled up. In this review, the following in vitro parameters are presented: frequency of spontaneous mutant selection (FSMS), mutant prevention concentration (MPC), dominant mutant prevention concentration (MPC-D), inferior-mutant prevention concentration (MPC-F), and minimal selective concentration (MSC). The utility of various adaptive laboratory evolution (ALE) approaches (serial transfer, continuous culture, and evolution in spatiotemporal microenvironments) for comparing hits in terms of the level and time required for multistep resistance to emerge is discussed. We also consider how the hit-to-lead stage can benefit from high-throughput ALE setups based on robotic workstations, do-it-yourself (DIY) continuous cultivation systems, microbial evolution and growth arena (MEGA) plates, soft agar gradient evolution (SAGE) plates, microfluidic chips, or microdroplet technology. Finally, approaches for evaluating the fitness of in vitro-generated resistant mutants are presented. This review aims to draw attention to newly emerged ideas on how to improve the in vitro forecasting of the potential of compounds to select for resistance in natural settings. [ABSTRACT FROM AUTHOR]

A series of 22 benzosiloxaboroles, silicon analogues of strong antimicrobial agents - benzoxaboroles, have been synthesized and tested against β-lactamases KPC- and pAmpC-producing strains of Gram-negative rods. Comprehensive structural-property relationship studies supported by molecular modelling as well as biological studies reveal that 6-B(OH) 2 -substituted derivative 27 strongly inhibits the activity of cephalosporinases (chromosomally encoded AmpC and plasmid encoded CMY-2) and KPC carbapenemases. It also shows strong ability to inhibit growth of the strains producing KPC-3 when combined with meropenem. In addition, halogen-substituted (mono-, di- or tetra-) benzosiloxaboroles demonstrate high antifungal activity (MIC 1.56–6.25 mg/L) against C. tropicalis , C. guilliermondii and S. cerevisiae. The highest activity against pathogenic yeasts (C. albicans , C. krusei and C. parapsilosis - MICs 12.5 mg/L) and against Gram-positive cocci (S. aureus and E. faecalis - 6.25 mg/L and 25 mg/L respectively) was displayed by 6,7-dichloro-substituted benzosiloxaborole. The studied systems exhibit low cytotoxity toward human lung fibroblasts. Image 1 • Synthesis and characterization of a series of 22 functionalized benzosiloxaboroles. • Strong antifungal activity of fluorinated derivatives. • KPC/AmpC inhibitory activity of selected benzosiloxaboroles. • Docking and molecular dynamics studies on the binding to the KPC-2 β-lactamase. [ABSTRACT FROM AUTHOR]

A series of new polyhalogenated benzimidazoles has been synthesized and their antibacterial and antiprotozoal activity was evaluated. Several of new substituted halogenobenzimidazoles and their 2′-deoxynucleosides showed noteworthy antiprotozoal toxicity particularly against Giardia lamblia. The most potent agents against bacteria and fungi were 4,5,6,7-tetrachlorobenzimidazoles with polyfluoroalkyl chain at position 2 of the heterocyclus. [ABSTRACT FROM AUTHOR]