Yusuke Minato

BACKGROUND: Flomoxef and cefmetazole have been reported to be effective against broad-spectrum β-lactamase-producing bacteria and have gained attention as a potential alternative to carbapenems. This study aimed to compare the efficacy of these two drugs in treating urinary tract infection (UTI) by integrating in vitro data and two real-world databases. METHODS: The susceptibility rates of third-generation cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae to flomoxef and cefmetazole were compared using comprehensive national antimicrobial resistance surveillance data. Combined antimicrobial activities against an extended-spectrum beta-lactamase (ESBL)-producing multidrug-resistant bacterial strain were tested by diagonal measurement of n-way drug interactions. The effectiveness of the two drugs in treating UTIs was compared using hospital stay duration data obtained from the Japan Medical Data Center (JMDC) Claims Database. RESULTS: Third-generation cephalosporin-resistant E. coli and K. pneumoniae, including ESBL-producing strains, were similarly susceptible to flomoxef and cefmetazole. In vitro assessment against an ESBL-producing multidrug-resistant strain revealed similar antimicrobial interaction patterns. JMDC Claims data analysis showed that the median hospital stay was 11 (95% confidence interval [CI]: 11-11) and 4 (95% CI: 3-5) days in the cefmetazole and flomoxef groups, respectively (log-rank test, P < 0.001). Moreover, the flomoxef group demonstrated a significantly lower frequency of adverse events such as C. difficile infection and renal failure. CONCLUSIONS: The effectiveness of flomoxef is comparable to that of cefmetazole in treating UTIs without major complications. Thus, flomoxef is a viable treatment option for UTIs in locales with a high prevalence of ESBL-producing strains.

OBJECTIVE: To examine the international trends for nontuberculous mycobacterial-associated mortality rates, as nontuberculous mycobacterial infections are becoming increasingly prevalent and pose a significant public health challenge, especially in older populations. METHODS: This retrospective observational study used data from the World Health Organization mortality database, which included patients with nontuberculous mycobacterial infection in 83 countries. We stratified the data by sex, age, and geographic region and calculated crude and age-standardized mortality rates to estimate long-term mortality trends. RESULTS: In total, 42,182 nontuberculous mycobacterial infection-associated deaths (58.1% in women) were reported in 83 countries between 2000 and 2022. The locally weighted regression model estimation for the nontuberculous mycobacterial infection-associated mortality rate more than doubled-from 0.36 deaths per 1,000,000 individuals in 2000 to 0.77 deaths per 1,000,000 individuals in 2022. Eighty-six percent of nontuberculous mycobacterial infection-associated deaths occurred in people aged ≥65 years. The mortality rate was the highest in the Western Pacific Region. CONCLUSIONS: This study highlights the impact of emerging nontuberculous mycobacterial diseases and the importance of targeted interventions for managing and reducing mortality, particularly in vulnerable older populations. Further studies are warranted to determine the factors contributing to geographical disparity and treatment options.

This study highlights the novel potential of molecular aggregates as inhibitors of a disease-related protein. Enzyme inhibitors have been studied and developed as molecularly targeted drugs and have been applied for cancer, autoimmune diseases, and infections. In many cases, enzyme inhibitors that are used for therapeutic applications interact directly with enzymes in a molecule-to-molecule manner. We found that the aggregates of a small compound, Mn007, inhibited bovine pancreatic DNase I. Once Mn007 molecules formed aggregates, they exhibited inhibitory effects specific to DNases that require divalent metal ions. A DNase secreted by Streptococcus pyogenes causes streptococcal toxic shock syndrome (STSS). STSS is a severe infectious disease with a fatality rate exceeding 30% in patients, even in this century. S. pyogenes disrupts the human barrier system against microbial infections through the secreted DNase. Until now, the discovery/development of a DNase inhibitor has been challenging. Mn007 aggregates were found to inhibit the DNase secreted by S. pyogenes, which led to the successful suppression of S. pyogenes growth in human whole blood. To date, molecular aggregation has been outside the scope of drug discovery. The present study suggests that molecular aggregation is a vast area to be explored for drug discovery and development because aggregates of small-molecule compounds can inhibit disease-related enzymes.

The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria.

The total synthesis of capuramycin (1), which is a promising anti-tubercular antibiotics, has been accomplished using Ferrier-type I reaction as a key step. This total synthesis is an alternative approach to the synthesis of capuramycin and its analogues. The 3'-O-demethyl analogue (2), which exhibits an equivalent antibacterial activity as capuramycin (1) against Mycobacterium smegmatis and Mycobacterium avium, is suggested to have potential as a lead structure of capuramycin analogues because 2 is more accessible from a synthetic view point.