Antibiotic resistance has progressively diminished the effectiveness of conventional antibiotics, necessitating the cessation of clinical treatment. Consequently, novel antibacterial agents are urgently needed. We review studies on antimicrobial agents published during 2002-2023. Most of these studies were published within the last 10 years. By analyzing recent articles on antibiotic resistance and the development of new antibacterial drugs, we showed that although drug resistance is inevitable, the issue is being addressed gradually via the discovery and clinical application of antimicrobial peptides, nanomaterial drugs, and bacteriophage therapy. In light of the emergence of antimicrobial resistance, the development of new antimicrobial agents will require innovation in a field that has relied on traditional methods of discovery and development.

OBJECTIVE: To investigate the association of potential risk factors for urinary tract infections (UTI) caused by E. coli producing ESBL vs. not producing ESBL in Iceland.
METHODS: Observational, case-control study including a cohort of 27,747 patients (22,800 females, 4,947 males; 1207 cases, 26,540 controls) of all ages with UTI caused by E. coli in 2012 to 2021 at the clinical microbiology laboratory covering about 2/3 of the Icelandic population. Clinical patient data was obtained from three national databases. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as a measure of association between ESBL and exposure variables.
RESULTS: The proportion of samples with ESBL-producing E. coli increased during the study period, from 2.6% in 2012 to 7.6% in 2021 (p < 0.001). ESBL-positive strains were detected in 1207 individuals (4.4%), 905 females (4.0%) and 302 males (6.1%). The following risk factors were identified: Male sex, higher age, institution type (hospital, nursing home), hospital-associated UTI, Charlson comorbidity index score ≥ 3, history of cystitis or hospitalization in the past year, and prescriptions for certain antibiotics or proton pump inhibitors (PPIs: OR 1.51) in the past half year. The antibiotic associated with the highest risk was ciprofloxacin (OR 2.45).
CONCLUSIONS: The prevalence of UTIs caused by ESBL-producing E. coli has been increasing in Iceland. The strongest risk factors for ESBL production were previous antibiotic use, especially ciprofloxacin, and previous PPI use, both considered to be overprescribed. It is important to promote the prudent use of these drugs.

With respect to other fields, bone tissue engineering has significantly expanded in recent years, leading not only to relevant advances in biomedical applications but also to innovative perspectives. Polycaprolactone (PCL), produced in the beginning of the 1930s, is a biocompatible and biodegradable polymer. Due to its mechanical and physicochemical features, as well as being easily shapeable, PCL-based constructs can be produced with different shapes and degradation kinetics. Moreover, due to various development processes, PCL can be made as 3D scaffolds or fibres for bone tissue regeneration applications. This outstanding biopolymer is versatile because it can be modified by adding agents with antimicrobial properties, not only antibiotics/antifungals, but also metal ions or natural compounds. In addition, to ameliorate its osteoproliferative features, it can be blended with calcium phosphates. This review is an overview of the current state of our recent investigation into PCL modifications designed to impair microbial adhesive capability and, in parallel, to allow eukaryotic cell viability and integration, in comparison with previous reviews and excellent research papers. Our recent results demonstrated that the developed 3D constructs had a high interconnected porosity, and the addition of biphasic calcium phosphate improved human cell attachment and proliferation. The incorporation of alternative antimicrobials-for instance, silver and essential oils-at tuneable concentrations counteracted microbial growth and biofilm formation, without affecting eukaryotic cells\' viability. Notably, this challenging research area needs the multidisciplinary work of material scientists, biologists, and orthopaedic surgeons to determine the most suitable modifications on biomaterials to design favourable 3D scaffolds based on PCL for the targeted healing of damaged bone tissue.

The development of antimicrobial drugs with novel structures and clear mechanisms of action that are active against drug-resistant bacteria has become an urgent need of safeguarding human health due to the rise of bacterial drug resistance. The discovery of AMPs and the development of amphipathic peptidomimetics have lay the foundation for novel antimicrobial agents to combat drug resistance due to their overall strong antimicrobial activities and unique membrane-active mechanisms. To break the limitation of AMPs, researchers have invested in great endeavors through various approaches in the past years. This review summarized the recent advances including the development of antibacterial small molecule peptidomimetics and peptide-mimic cationic oligomers/polymers, as well as mechanism-of-action studies. As this exciting interdisciplinary field is continuously expanding and growing, we hope this review will benefit researchers in the rational design of novel antimicrobial peptidomimetics in the future.

Diarrhoea remains an important public health concern, particularly in developing countries, and has become difficult to treat because of antibacterial resistance. The development of synergistic antimicrobial agents appears to be a promising alternative treatment against diarrhoeic infections. In this study, the combined effect of tetracycline together with either nitroxoline, sanguinarine, or zinc pyrithione (representing various classes of plant-based compounds) was evaluated in vitro against selected diarrhoeic bacteria (Enterococcus faecalis, Escherichia coli, Listeria monocytogenes, Shigella flexneri, Vibrio parahaemolyticus, and Yersinia enterocolitica). The chequerboard method in 96-well microtiter plates was used to determine the sum of the fractional inhibitory concentration indices (FICIs). Three independent experiments were performed per combination, each in triplicate. It was observed that the combination of tetracycline with either nitroxoline, sanguinarine, or zinc pyrithione produced synergistic effects against most of the pathogenic bacteria tested, with FICI values ranging from 0.086 to 0.5. Tetracycline-nitroxoline combinations produced the greatest synergistic action against S. flexneri at a FICI value of 0.086. The combinations of the agents tested in this study can thus be used for the development of new anti-diarrhoeic medications. However, studies focusing on their in vivo anti-diarrhoeic activity and safety are required before any consideration for utilization in human medicine.

Recently, the days of antibiotic spectrum coverage (DASC) using the antibiotic spectrum coverage (ASC) score was reported as a new tool for measuring antimicrobial use. The days of therapy (DOT) are required to calculate the DASC, making it impossible to use when patient-level information is unavailable. Therefore, we have defined a new measure of antimicrobial use for antimicrobial spectrum coverage (AUSC) using antimicrobial use density (AUD) and ASC scores. In this study, we have investigated the use of antimicrobial agents retrospectively examined for monthly prescriptions between 2016 and 2022, and whether the AUSC could be used as a new measure. Our data showed that the AUD, AUSC, DOT, and DASC increased, whereas AUSC/AUD and DASC/DOT decreased over the study period. In addition, no correlation was found between DOT and DASC/DOT (ρ = - 0.093, p = 0.399), whereas there was a weak correlation between AUD and AUSC/AUD (ρ = - 0.295, p = 0.006). Therefore, in this study, the use of AUSC is considered less beneficial when DASC can be calculated based on DOT. On the other hand, in institutional settings where DOT cannot be calculated, AUSC may be useful as a new measure to evaluate antimicrobial use.

Mannheimia haemolytica is a major contributor to bovine respiratory disease (BRD), which causes substantial economic losses to the beef industry, and there is an urgent need for rapid and accurate diagnostic tests to provide evidence for treatment decisions and support antimicrobial stewardship. Diagnostic sequencing can provide information about antimicrobial resistance genes in M. haemolytica more rapidly than conventional diagnostics. Realizing the full potential of diagnostic sequencing requires a comprehensive understanding of the genetic markers of antimicrobial resistance. We identified genetic markers of resistance in M. haemolytica to macrolide class antibiotics commonly used for control of BRD. Genome sequences were determined for 99 M. haemolytica isolates with six different susceptibility phenotypes collected over 2 years from a feedlot in Saskatchewan, Canada. Known macrolide resistance genes estT, msr(E), and mph(E) were identified in most resistant isolates within predicted integrative and conjugative elements (ICEs). ICE sequences lacking antibiotic resistance genes were detected in 10 of 47 susceptible isolates. No resistance-associated polymorphisms were detected in ribosomal RNA genes, although previously unreported mutations in the L22 and L23 ribosomal proteins were identified in 12 and 27 resistant isolates, respectively. Pangenome analysis led to the identification of 79 genes associated with resistance to gamithromycin, of which 95% (75 of 79) had no functional annotation. Most of the observed phenotypic resistance was explained by previously identified antibiotic resistance genes, although resistance to the macrolides gamithromycin and tulathromycin was not explained in 39 of 47 isolates, demonstrating the need for continued surveillance for novel determinants of macrolide resistance.IMPORTANCEBovine respiratory disease is the costliest disease of beef cattle in North America and the most common reason for injectable antibiotic use in beef cattle. Metagenomic sequencing offers the potential to make economically significant reductions in turnaround time for diagnostic information for evidence-based selection of antibiotics for use in the feedlot. The success of diagnostic sequencing depends on a comprehensive catalog of antimicrobial resistance genes and other genome features associated with reduced susceptibility. We analyzed the genome sequences of isolates of Mannheimia haemolytica, a major bovine respiratory disease pathogen, and identified both previously known and novel genes associated with reduced susceptibility to macrolide class antimicrobials. These findings reinforce the need for ongoing surveillance for markers of antimicrobial resistance to support improved diagnostics and antimicrobial stewardship.

BACKGROUND: The approval of Sucrose Fatty Acid Esters (SFAEs) as food additives/ preservatives with antimicrobial potential has triggered enormous interest in discovering new biological applications. Accordingly, many researchers reported that SFAEs consist of various sugar moieties, and hydrophobic side chains are highly active against certain fungal species.
OBJECTIVE: This study aimed to conduct aregioselective synthesis of SAFE and check the effect of chain length and site of acylation (i.e., C-6 vs. C-2, C-3, C-4, and long-chain vs. short-chain) on antimicrobial potency.
METHODS: A direct acylation method maintaining several conditions was used for esterification. In vitro tests, molecular docking, and in silico studies were conducted using standard procedures.
RESULTS: In vitro tests revealed that the fatty acid chain length in mannopyranoside esters significantly affects the antifungal activity, where C12 chains are more potent against Aspergillus species. In terms of acylation site, mannopyranoside esters with a C8 chain substituted at the C-6 position are more active in antifungal inhibition. Molecular docking also revealed that these mannopyranoside esters had comparatively better stable binding energy and hence better inhibition, with the fungal enzymes lanosterol 14-alpha-demethylase (3LD6), urate oxidase (1R51), and glucoamylase (1KUL) than the standard antifungal drug fluconazole. Additionally, the thermodynamic, orbital, drug-likeness, and safety profiles of these mannopyranoside esters were calculated and discussed, along with the Structure-Activity Relationships (SAR).
CONCLUSIONS: This study thus highlights the importance of the acylation site and lipid-like fatty acid chain length that govern the antimicrobial activity of mannopyranoside-based SFAE.

Rising antimicrobial resistance is a critical threat to worldwide public health. To address the increasing antibiotic tolerance, diverse antimicrobial agents are examined for their ability to decrease bacterial resistance. One of the most relevant and persistent human pathogens is Pseudomonas aeruginosa. Our study investigates the anti-biofilm and sensitizing activity of 12 morpholinium-based ionic liquids with herbicidal anions on four clinically relevant P. aeruginosa strains. Among all tested compounds, four ionic liquids prevented biofilm formation at sub-minimum inhibitory concentrations for all investigated strains. For the first time, we established a hormetic effect on biofilm formation for P. aeruginosa strains subjected to an ionic liquid treatment. Interestingly, while ionic liquids with 4,4-didecylmorpholinium [Dec2Mor]+ are more efficient against planktonic bacteria, 4-decyl-4-ethylmorpholinium [DecEtMor]+ showed more potent inhibition of biofilm formation. Ionic liquids with 4,4-didecylmorpholinium ([Dec2Mor]+) cations even induced biofilm formation by strain 39016 at high concentrations due to flocculation. Morpholinium-based ionic liquids were also shown to enhance the efficacy of commonly used antibiotics from different chemical groups. We demonstrate that this synergy is associated with the mode of action of the antibiotics.

Postbiotic is the term used to define the soluble factors, metabolic products, or byproducts released by live probiotic bacteria or after its lysis. The objective of this study was to carry out the chemical characterization of the postbiotic of Lacticaseibacillus rhamnosus LR-32 and to evaluate its in vitro effect on the development of the Streptococcus mutans biofilm. After the cultivation of the probiotic strain, the postbiotic was extracted by centrifuging the culture and filtering the supernatant. This postbiotic was characterized by using gas chromatography coupled with mass spectrometry (GC-MS), and then it was used to determine the growth inhibition of S. mutans in its planktonic form; additionally, its effects on the following parameters in 48 h biofilm were evaluated: viable bacteria, dry weight, and gene expression of glucosyltransferases and VicR gene. The control group consisted of the biofilm without any treatment. A paired t-test was performed for statistical analysis, with the p-value set at 5%. Seventeen compounds of various chemical classes were identified in the postbiotic, including sugars, amino acids, vitamins, and acids. The treatment with the postbiotic led to an inhibition of the growth of S. mutans in its planktonic form, as well as a decrease in the number of viable bacteria, reduction in dry weight, and a negative regulation of the gene expression of gtfB, gtfC, gtfD, and vicR in its biofilm state, compared with the nontreated group (p < 0.05). The postbiotic of L. rhamnosus impaired the development of S. mutans biofilm.