Decoding Antibiotic Resistance: OprD Allels in Pseudomonas aeruginosa and their Impact on Carbapenem Resistance

Pseudomonas aeruginosa, commonly isolated from hospitalized patients, poses a significant therapeutic challenge due to its intrinsic and acquired antibiotic resistance. Carbapenems, crucial in treatment, often fail to eradicate the pathogen due to resistance associated with mutations in the outer membrane porin D (OprD). This study seeks to elucidate the impact of distinct OprD alleles (amino acid sequences) on carbapenem resistance, aiming to establish OprD as a reliable genetic predictor.

A dataset comprising 4,875 clinical isolates collected unbiased from a German and a Danish hospital, underwent susceptibility testing against imipenem and meropenem and whole genome sequencing. The analyzed isolates contained 192 distinct OprD alleles, with the most common variant occurring in 20.7 % of the isolates. Of the 4,875 isolates 46.7 % decoded an OprD sequence of conserved-length (441-446 amino acids). There were in total 41 different conserved-length Oprd variants. The fact that a clinical P. aeruginosa isolates does not contain a conserved-length allele showed unexpectedly high accuracy in predicting the antimicrobial resistance for both imipenem (sensitivity: 0.731; specificity: 0.962) and meropenem (0.764; 0.934).
Further analysis focused on common OprD variants that were found in at least 10 clinical isolates (30 OprD variants) and revealed significant differences in their individual impact on carbapenem resistance. Interestingly, there are also variants that are exclusively predictive for antimicrobial resistance of either imipenem or meropenem.

The results again underline that OprD is the most common driver of carbapenem resistance in P. aeruginosa in terms of non-acquired resistance and it is the first time that OprD alleles have been analyzed in >1,000 isolates. We found that inactivation of OprD is usually caused by an early stop codon or a frameshift mutation and rarely by single amino acid exchanges.