Whole genome sequence analysis of Helicobacter pylori isolates reveals incomplete characterization of antimicrobial resistance mechanisms

<i>Helicobacter pylori</i>, one of the most common causes of chronic bacterial infections worldwide and a carcinogen, has been associated with significant antimicrobial resistance. Here, whole genome sequencing and phenotypic susceptibility testing to amoxicillin, clarithromycin, levofloxacin, metronidazole, rifampin, and tetracycline of 530 <i>H. pylori</i> clinical isolates revealed significant genomic diversity not clustered by geographic location in the United States, and genome-wide association studies revealed incomplete genotypic characterization of antimicrobial resistance mechanisms for amoxicillin, metronidazole, and rifampin. Resistance to amoxicillin, metronidazole, and rifampin was not associated with a particular single-nucleotide polymorphism, the number of mutations in resistant versus susceptible isolates, or a particular mutation hotspot in a gene previously implicated in resistance. This study highlights a need for further elucidation of the genetic basis of antimicrobial resistance (beyond clarithromycin and levofloxacin) in this species.