High-level nitrofurantoin resistance in a clinical isolate of Klebsiella pneumoniae: a comparative genomics and metabolomics analysis

• Published in: mSystems 2024-01, Vol.9 (1), p.e0097223
• Main Authors: Hussein, Maytham, Sun, Zetao, Hawkey, Jane, Allobawi, Rafah, Judd, Louise M, Carbone, Vincenzo, Sharma, Rajnikant, Thombare, Varsha, Baker, Mark, Rao, Gauri G, Li, Jian, Holt, Kathryn E, Velkov, Tony
• Format: Article
• Language: English
• Subjects: Antibacterial activity; Antibiotics; Antimicrobial Chemotherapy; antimicrobial resistance; Biosynthesis; Carbohydrate metabolism; E coli; Genes; Genomes; Genomics; Gram-negative bacteria; Klebsiella pneumoniae; Metabolic pathways; Metabolomics; Microbial Genomics; Multidrug resistance; Mutation; Nitrofurantoin; Nitroreductase; Nosocomial infections; Pathogens; Pharmacophores; Proteins; Resistant mutant; Riboflavin; tRNA; Urinary tract; Urinary tract infections; Whole genome sequencing
• ISSN: 2379-5077; 2379-5077
• DOI: 10.1128/msystems.00972-23

A quest for novel antibiotics and revitalizing older ones (such as nitrofurantoin) for treatment of difficult-to-treat Gram-negative bacterial infections has become increasingly popular. The precise antibacterial activity of nitrofurantoin is still not fully understood. Furthermore, although the prevalence of nitrofurantoin resistance remains low currently, the drug's fast-growing consumption worldwide highlights the need to comprehend the emerging resistance mechanisms. Here, we used multidisciplinary techniques to discern the exact mechanism of nitrofurantoin action and high-level resistance in , a common cause of urinary tract infections for which nitrofurantoin is the recommended treatment. We found that the expression of multiple genes related to membrane transport (including active efflux and passive diffusion of drug molecules) and nitroreductase activity was modified in nitrofurantoin-resistant strains, including oqxR, the transcriptional regulator of the oqxAB efflux pump. Furthermore, complex interconnected metabolic pathways that potentially govern the nitrofurantoin-killing mechanisms (e.g., aminoacyl-tRNA biosynthesis) and nitrofurantoin resistance (riboflavin metabolism) were significantly inhibited following nitrofurantoin treatment. Our study could help inform the improvement of nitrofuran derivatives, the development of new pharmacophores, or drug combinations to support the resurgence of nitrofurantoin in the management of multidrug resistant infection.