UNASSIGNED: The rise of antibiotic-resistant Streptococcus pneumoniae (Sp) poses a significant global health threat, urging the quest for novel antimicrobial solutions. We have discovered that the human hormone l-thyroxine has antibacterial properties. In order to explore its drugability we perform here the characterization of a series of l-thyroxine analogues and describe the structural determinants influencing their antibacterial efficacy.
UNASSIGNED: We performed a high-throughput screening of a library of compounds approved for use in humans, complemented with ITC assays on purified Sp-flavodoxin, to pinpoint molecules binding to this protein. Antimicrobial in vitro susceptibility assays of the hit compound (l-thyroxine) as well as of 13 l-thyroxine analogues were done against a panel of Gram-positive and Gram-negative bacteria. Toxicity of compounds on HepG2 cells was also assessed. A combined structure-activity and computational docking analysis was carried out to uncover functional groups crucial for the antimicrobial potency of these compounds.
UNASSIGNED: Human l-thyroxine binds to Sp-flavodoxin, forming a 1:1 complex of low micromolar Kd. While l-thyroxine specifically inhibited Sp growth, some derivatives displayed activity against other Gram-positive bacteria like Staphylococcus aureus and Enterococcus faecalis, while remaining inactive against Gram-negative pathogens. Neither l-thyroxine nor some selected derivatives exhibited toxicity to HepG2 cells.
UNASSIGNED: l-thyroxine derivatives targeting bacterial flavodoxins represent a new and promising class of antimicrobials.

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Respiratory complex I is a multicomponent enzyme conserved between eukaryotic cells and many bacteria, which couples oxidation of electron donors and quinone reduction with proton pumping. Here, we report that protein transport via the Cag type IV secretion system, a major virulence factor of the Gram-negative bacterial pathogen Helicobacter pylori, is efficiently impeded by respiratory inhibition. Mitochondrial complex I inhibitors, including well-established insecticidal compounds, selectively kill H. pylori, while other Gram-negative or Gram-positive bacteria, such as the close relative Campylobacter jejuni or representative gut microbiota species, are not affected. Using a combination of different phenotypic assays, selection of resistance-inducing mutations, and molecular modeling approaches, we demonstrate that the unique composition of the H. pylori complex I quinone-binding pocket is the basis for this hypersensitivity. Comprehensive targeted mutagenesis and compound optimization studies highlight the potential to develop complex I inhibitors as narrow-spectrum antimicrobial agents against this pathogen.

The development of broad-spectrum antibiotics to control multidrug-resistant bacteria is an outdated business model. This strategy has led to the introduction of highly effective antibiotics, but their widespread use has contributed to the emergence of even broader antibiotic resistance. In a strategy to combat antimicrobial resistance, we believe that the use of narrow-spectrum antibiotics should be promoted. This should involve both the repositioning of old antibiotics and the reorientation of research and development towards new narrow-spectrum antibiotics with a low ecological impact. These antibiotics could be prescribed for common conditions such as sore throats and cystitis, which account for the bulk of antibiotic use in humans. Narrow-spectrum, targeted, microbiome-sparing antibiotics could help control antibiotic resistance while being economically sustainable. Their development and production should be supported by governments, which would ultimately benefit from reduced health care costs.

Clostridioides difficile (Cdiff) infection (CDI) continues to be the leading threat of nosocomial deaths worldwide and a major burden on health-care systems. Broad-spectrum antibiotics eradicate the normal gut microbiome, killing protective commensal bacteria and increasing CDI recurrence. In contrast, Fidaxomicin (Fdx) is a narrow-spectrum antibiotic that inhibits Cdiff growth without affecting crucial gut microbes. However, the basis of the narrow-spectrum activity of Fdx on its target, RNA polymerase (RNAP), in Cdiff has been enigmatic. Recently, Cao et al. (Nature, doi: 10.1038/s41586-022-04545-z) combined transgenic RNAP design and synthesis with cryo-electron microscopy (cryo-EM) to identify a key determinant of Fdx inhibition of Cdiff RNAP. This finding was further corroborated by biochemical, bioinformatics, and genetic analysis. This microreview describes implications of this work for lineage-specific antibiotic design and new directions toward understanding transcription and regulation in Cdiff and other bacterial pathogens.

The rapid rise of antibiotic resistance is a serious threat to global public health. The situation is exacerbated by the \"antibiotics dilemma\": Developing narrow-spectrum antibiotics against resistant bacteria is most beneficial for society, but least attractive for companies, since their usage and sales volumes are more limited than for broad-spectrum drugs. After developing a general mathematical framework for the study of antibiotic resistance dynamics with an arbitrary number of antibiotics, we identify efficient treatment protocols. Then, we introduce a market-based refunding scheme that incentivizes pharmaceutical companies to develop new antibiotics against resistant bacteria and, in particular, narrow-spectrum antibiotics that target specific bacterial strains. We illustrate how such a refunding scheme can solve the antibiotics dilemma and cope with various sources of uncertainty that impede antibiotic R &D. Finally, connecting our refunding approach to the recently established Antimicrobial Resistance (AMR) Action Fund, we discuss how our proposed incentivization scheme could be financed.

Acinetobacter baumannii has emerged as one of the most lethal drug-resistant bacteria in recent years. We report the synthesis and antimicrobial studies of 25 new pyrazole-derived hydrazones. Some of these molecules are potent and specific inhibitors of A. baumannii strains with a minimum inhibitory concentration (MIC) value as low as 0.78 µg/mL. These compounds are non-toxic to mammalian cell lines in in vitro studies. Furthermore, one of the potent molecules has been studied for possible in vivo toxicity in the mouse model and found to be non-toxic based on the effect on 14 physiological blood markers of organ injury.

We sought to compare the effectiveness of narrow- versus broad-spectrum antibiotics (abx) in preventing infectious complications in adults with acute appendicitis treated with appendectomy.
In this post hoc analysis of a prospective multicenter observational study of appendicitis in adults (≥18 y) conducted from January 2017 to June 2018, we included only patients with simple appendicitis. Subjects were grouped based on receipt of broad-spectrum or narrow-spectrum abx before and/or after appendectomy. Outcomes compared were surgical site infection, intra-abdominal abscess, secondary interventions (percutaneous drainage or operation), emergency department (ED) visits, 30-d readmission, and hospital length of stay.
A total of 2336 subjects were analyzed. In comparing narrow (n = 778) versus broad (n = 1558) groups, there were no differences in male sex (53% versus 54%, P = 0.704), white blood cell (13.0 ± 3.9 versus 13.4 ± 4.5, P = 0.05), Alvarado score (6 [5-7] versus 6 [5-7], P = 0.25), or Charlson comorbidity index (0 [0-1] versus 0 [0-1], P = 0.09). A total of 688 (29%) received postoperative abx, [184 (24%) narrow and 504 (32%) broad, P < 0.001] for a median 5 [2-7] d [42 (23%) narrow and 235 (47%) broad, P < 0.001]. There were no significant differences between narrow and broad groups in surgical site infection, intra-abdominal abscess, secondary interventions, ED visits, or hospital readmissions.
Significant practice variation in duration and spectrum of antibiotic adjunct for surgical treatment of simple acute appendicitis treatment is evident, and broad-spectrum abx did not offer clinical advantages over narrow-spectrum abx. Restriction of antibiotic spectrum should be considered, although randomized trials are required to overcome selection bias.

We carried out a retrospective cohort study on patients with advanced cancer treated with immune checkpoint inhibitors (ICIs) to determine whether antibiotics affect treatment outcome. Sixty consecutive patients were identified, and 17 received systemic antibiotics within 2 weeks before and/or after first dose of ICI. Antibiotic-treated patients were significantly younger (p = 0.0008) and less likely to receive nivolumab (p = 0.08) or had neutrophil:lymphocyte ratio < 5 (p = 0.08). They had a lower response rate (RR) (29.4% vs 62.8%) (p = 0.024) and more inferior progression-free survival (PFS) (p = 0.048). Narrow-spectrum antibiotics did not affect the RR. However, broad-spectrum antibiotics were associated with a lower RR (25% vs 61%) (p = 0.02) and a trend towards longer time to response (median: 14 weeks vs 12 weeks) (p = 0.1). They also had shorter PFS (p = 0.012). Multivariate analysis identified antibiotics as the only factor affecting RR (p = 0.0038) and PFS (p = 0.01). We next examined the 21 patients whose PFS lasted for 12 weeks or more. Five of the 21 patients received broad-spectrum antibiotics within 10 weeks before disease progression. There was a trend towards shorter PFS in these patients (p = 0.1). Finally, antibiotic-treated patients experienced shorter overall survival (OS) (median: 24 months vs 89 months) (p = 0.003). Multivariate analysis found age (p = 0.035) and antibiotics (p = 0.038) to be the only factors affecting OS. Our results point to a detrimental effect of broad-spectrum antibiotics on treatment outcome to ICI therapy.