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Antimicrobial resistance (AMR) is one of the top ten threats to public health, as reported by the World Health Organization (WHO). One of the causes of the growing AMR problem is the lack of new therapies and/or treatment agents; consequently, many infectious diseases could become uncontrollable. The need to discover new antimicrobial agents that are alternatives to the existing ones and that allow mitigating this problem has increased, due to the rapid and global expansion of AMR. Within this context, both antimicrobial peptides (AMPs) and cyclic macromolecules, such as resorcinarenes, have been proposed as alternatives to combat AMR. Resorcinarenes present multiple copies of antibacterial compounds in their structure. These conjugate molecules have exhibited antifungal and antibacterial properties and have also been used in anti-inflammatory, antineoplastic, and cardiovascular therapies, as well as being useful in drug and gene delivery systems. In this study, it was proposed to obtain conjugates that contain four copies of AMP sequences over a resorcinarene core. Specifically, obtaining (peptide)4-resorcinarene conjugates derived from LfcinB (20–25): RRWQWR and BF (32–34): RLLR was explored. First, the synthesis routes that allowed obtaining: (a) alkynyl-resorcinarenes and (b) peptides functionalized with the azide group were established. These precursors were used to generate (c) (peptide)4-resorcinarene conjugates by azide-alkyne cycloaddition CuAAC, a kind of click chemistry. Finally, the conjugates' biological activity was evaluated: antimicrobial activity against reference strains and clinical isolates of bacteria and fungi, and the cytotoxic activity over erythrocytes, fibroblast, MCF-7, and HeLa cell lines. Our results allowed establishing a new synthetic route, based on click chemistry, for obtaining macromolecules derived from resorcinarenes functionalized with peptides. Moreover, it was possible to identify promising antimicrobial chimeric molecules that may lead to advances in the development of new therapeutic agents. [ABSTRACT FROM AUTHOR]

A chimeric peptide derived from Lactoferricin B (LfcinB) and Buforin II (BFII) was designed. It specifically contains the reported antimicrobial minimal motif sequences LfcinB (20–25): RRWQWR and BFII (32–35): RLLR. The chimeric peptide was synthesized by intramolecular cyclization with a triazole bridge. The Chimera 3 exhibited higher antimicrobial activity against E. coli ATCC 25922 (MIC 93 μM) and S. aureus ATCC 25923 (93 μM) than the original sequences. Furthermore, it did not exhibit a significant hemolytic effect. [ABSTRACT FROM AUTHOR]

Objectives: To generate evidence-based recommendations through formal consensus regarding the treatment of upper urinary tract infections during gestation., Materials and Methods: Experts in microbiology, public health, internal medicine, infectious diseases, obstetrics, maternal fetal medicine and obstetric and gynecological infections participated in the consensus development group. The group also included professionals with training in clinical epidemiology, systematic data search, and representatives from the Health Secretariat and the Bogota Obstetrics and Gynecology Association. The participants disclosed their conflicts of interest. Starting with a clinical question, outcomes were graded and a systematic search was conducted in the Medline via PubMed, Embase, Lilacs, and Bireme databases. The search was expanded to include institutional repositories and antimicrobial resistance surveillance systems, with no language or date restrictions. The search was updated on October 1, 2022. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to assess the quality of the evidence and determine the strength of the recommendations. Finally, the RAND/UCLA (Research and Development/University of California Los Angeles) methodology was applied for the formal consensus. This document was reviewed by academic peers before publication., Results: The following are the consensus recommendations. Recommendation 1. The initial management of pregnant women with upper urinary tract infections (UTIs) should be approached in a hospital setting. Recommendation 2. The use of second generation cephalosporins is the suggested first option for empirical antimicrobial management in pregnant women with upper UTI in order to improve the rates of clinical and microbiological cure. Recommendation 3. Because of the risk-benefit balance, the use of aminoglycosides is suggested as a second option for empirical antimicrobial treatment in pregnant women presenting with upper UTIs in the second and third trimester. Recommendation 4. The use of third-generation cephalosporins is suggested as the third option for empirical antimicrobial treatment in pregnant women with upper UTIs given that the risk of inducing microbial resistance is high with this group of antibiotics. Recommendation 5. The use of carbapenems is suggested as a first option in pregnant women with upper UTIs and a history of infections caused by microorganisms with resistance to third or fourth-generation cephalosporins. Recommendation 6. The use of aminoglycosides or fourth-generation cephalosporins is suggested as a second option in pregnant women with upper UTIs and a history of infection caused by microorganisms with resistance to third-generation cephalosporins, taking risk-benefit into account. Recommendation 7. The use of piperacillin/tazobactam is suggested as a third option in pregnant women with upper UTIs and a history of infection caused by microorganisms with resistance to third or fourthgeneration cephalosporins. Recommendation 8. Getting a urine culture is recommended in pregnant women with upper UTIs before initiating empirical antimicrobial treatment. Recommendation 9. In pregnant women with upper UTIs, it is suggested to modify therapy in accordance with the results of the sensitivity test when the culture report shows resistance to the antimicrobial agent initiated empirically. Recommendation 10. In pregnant women hospitalized due to upper UTIs, it is suggested to switch to oral antimicrobial therapy after at least 48 hours of modulation of the systemic inflammatory response and the clinical signs of infection, and when tolerance to oral intake is adequate. Recommendation 11. In pregnant women with upper UTIs with no complications secondary to the primary infection, it is recommended to administer antibiotic therapy for a period of 7 to 10 days., Conclusions: It is expected that with this Colombian upper UTI consensus variability in clinical practice will be reduced. It is recommended that groups doing research in maternal fetal medicine assess the implementation and effectiveness of these recommendations.

Linear, dimeric, tetrameric, and cyclic peptides derived from lactoferricin B, containing the RRWQWR motif, were designed, synthesized, purified, and characterized using RP-HPLC chromatography and MALDI-TOF mass spectrometry. The antibacterial activity of the designed peptides against E. coli (ATCC 11775 and 25922) and their cytotoxic effect against MDA-MB-468 and MDA-MB-231 breast cancer cell lines were evaluated. Dimeric and tetrameric peptides showed higher antibacterial activity in both bacteria strains than linear peptides. The dimeric peptide (RRWQWR)₂K-Ahx exhibited the highest antibacterial activity against the tested bacterial strains. Furthermore, the peptides with high antibacterial activity exhibited significant cytotoxic effect against the tested breast cancer cell lines. This cytotoxic effect was fast and dependent on the peptide concentration. The tetrameric molecule containing RRWQWR motif has an optimal cytotoxic effect at a concentration of 22 µM. The evaluated dimeric and tetrameric peptides could be considered as candidates for developing new therapeutic agents against breast cancer. Polyvalence of linear sequences could be considered as a novel and versatile strategy for obtaining molecules with high anticancer activity., Competing Interests: The authors declare no conflict of interest.