Amplification of Aminoglycoside Modifying Enzyme aadB Results in Tobramycin Heteroresistance Open Access

Abbott, Carter (Spring 2021)

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Antibiotic resistance is a major threat to healthcare. It is estimated that by 2050, ten million people will die per year due to infection by an antibiotic resistant pathogen. Due to this threat, the mechanisms behind antibiotic resistance must be studied in full. Heteroresistance, an understudied mechanism of antibiotic resistance, is the occurrence of a subpopulation of bacteria that are resistant to an antibiotic while the remaining population is susceptible. Antimicrobial susceptibility tests used in hospital clinics often are unable to detect resistant subpopulations, thus, heteroresistance is of unique interest. The inability to detect the resistant subpopulation may result in antibiotic treatment failure, complicating patient care. Of particular concern is tobramycin heteroresistance; tobramycin is an aminoglycoside that serves as a last line of defense antibiotic. In this study, we focus on the amplification of the aminoglycoside modifying enzyme, aadB, which results in tobramycin heteroresistance. We aim to investigate the prevalence and mechanisms surrounding the amplification of aadB. We report that 32% of the carbapenem-resistant Acinetobacter baumannii isolates contain aadB and that 56% of these isolates amplify the gene. Additionally, utilizing the tobramycin heteroresistant, carbapenem-resistant Enterobacter cloacae strain Mu1307, we establish that the inverted repeats that flank aadB are essential for its amplification. Finally, using a murine infection model, we demonstrate that treatment with tobramycin results in selection for aadB amplification, offering insight into why amplification of a resistance gene may result in treatment failure.

Table of Contents

Introduction                                                                                                                        1

Methods                                                                                                                                6

Results                                                                                                                                   8

Discussion                                                                                                                           15

Supplemental Figures                                                                                                       17

References                                                                                                                         18

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