The global dissemination of carbapenem-resistant Enterobacterales (CRE) poses a serious public health threat with limited treatment options. While carbapenemases are the predominant cause, there is increased diversification of the mechanisms leading to carbapenem resistance. Recent studies reveal the increasingly important role of porin channel disruptions in carbapenem resistance which alone are insufficient but can achieve such when present together with common beta-lactamases. We determined the potency of imipenem combined with relebactam, a novel class A/C beta-lactamase inhibitor, and comparator beta-lactams against the porin gene variants characteristic of highly drug-resistant clones of Klebsiella pneumoniae and antibiotic resistance genotypes. Broth microdilution testing was carried out with imipenem with/out relebactam at 4µg/ml and for ertapenem, meropenem, ceftazidime and ceftriaxone against 109 clinical isolates of Klebsiella pneumoniae from Australia, Italy and Brazil with porin defects and multiple antibiotic resistance profile. Resistance genes and porin mutations were established by whole-genome sequencing or target PCRs. A further 54 isogenic mutant constructs of ATCC 13883 and clinical isolate 10.85 with single or double porin defects in the OmpK35 or OmpK36 channels with/out selected beta-lactamases blaCTX-M-15, blaIMP-4, blaKPC-2 or blaCMY-2 were also studied for the antibiotic activity. There was a high prevalence of blaKPC genes (n=72) among the clinical isolates. Relebactam significantly enhanced the activity of imipenem with 93% of the clinical isolates showing susceptibility to the combination. There was limited activity against the OXA-48 producing isolates (n=7) with only two isolates showing reduced MICs with the addition of relebactam while there was no activity against the single IMP-4 producing isolate. All the tested antibiotics had good coverage against the isogenic porin mutants but the MICs were affected in those with compound porin defects together with beta-lactamase enzymes.