Sophisticated natural products as antibiotics.

In this Review, we explore natural product antibiotics that do more than simply inhibit an active site of an essential enzyme. We review these compounds to provide inspiration for the design of much-needed new antibacterial agents, and examine the complex mechanisms that have evolved to effectively target bacteria, including covalent binders, inhibitors of resistance, compounds that utilize self-promoted entry, those that evade resistance, prodrugs, target corrupters, inhibitors of 'undruggable' targets, compounds that form supramolecular complexes, and selective membrane-acting agents. These are exemplified by ß-lactams that bind covalently to inhibit transpeptidases and ß-lactamases, siderophore chimeras that hijack import mechanisms to smuggle antibiotics into the cell, compounds that are activated by bacterial enzymes to produce reactive molecules, and antibiotics such as aminoglycosides that corrupt, rather than merely inhibit, their targets. Some of these mechanisms are highly sophisticated, such as the preformed ß-strands of darobactins that target the undruggable ß-barrel chaperone BamA, or teixobactin, which binds to a precursor of peptidoglycan and then forms a supramolecular structure that damages the membrane, impeding the emergence of resistance. Many of the compounds exhibit more than one notable feature, such as resistance evasion and target corruption. Understanding the surprising complexity of the best antimicrobial compounds provides a roadmap for developing novel compounds to address the antimicrobial resistance crisis by mining for new natural products and inspiring us to design similarly sophisticated antibiotics.

Effect of ß-lactam antibiotics on the gut microbiota of term neonates.

ß-Lactam antibiotics are a class of antibiotics commonly used to treat bacterial infections. However, the effects of ß-lactam antibiotics on term neonatal intestinal flora have not been fully elucidated. Hospitalized full-term newborns receiving ß-lactam antibiotics formed the antibiotic group (n = 67), while those without antibiotic treatment comprised the non-antibiotic group (n = 47). A healthy group included healthy full-term newborns (n = 16). Stool samples were collected for 16 S rDNA sequencing to analyze gut microbiota variations. Further investigation was carried out within the ß-lactam antibiotic group, exploring the effects of antibiotic use on the newborns' gut microbiota in relation to the duration and type of antibiotic administration, delivery method, and feeding practices. The antibiotic group exhibited significant difference of microbial community composition compared to the other groups. Genera like Klebsiella, Enterococcus, Streptococcus, Alistipes, and Aeromonas were enriched, while Escherichia-Shigella, Clostridium sensu stricto 1, Bifidobacterium, and Parabacteroides were reduced. Klebsiella negatively correlated with Escherichia-Shigella, positively with Enterobacter, while Escherichia-Shigella negatively correlated with Enterococcus and Streptococcus. Regardless of neonatal age, ß-lactam antibiotics induced an elevated abundance of Klebsiella and Enterococcus. The impact on gut microbiota varied with the duration and type of antibiotic (cefotaxime or ampicillin/sulbactam). Compared to vaginal delivery, cesarean delivery after ß-lactam treatment heightened the abundance of Klebsiella, Enterobacteriaceae_Unclassified, Lactobacillales_Unclassified, and Pectobacterium. Feeding patterns minimally influenced ß-lactam-induced alterations. In conclusion, ß-lactam antibiotic treatment for neonatal pneumonia and sepsis markedly disrupted intestinal microbiota, favoring Klebsiella, Enterococcus, Streptococcus, Alistipes, and Aeromonas. The impact of ß-lactam varied by duration, type, and delivery method, emphasizing heightened disruptions post-cesarean delivery.