TABLE 2.

Effect of inactivation of carbapenem-specific porin OprD or permeabilization of outer membrane on potency of QPX7728 against P. aeruginosa^a

Strainb	Genotype	Antibiotic	Antibiotic MIC (μg/ml) in the presence of the following concn of QPX7728 (μg/ml)c:								MIC (μg/ml) for vector-only control	PVmax (μg/ml)
			0	0.125	0.25	0.5	1	2	4	8
PAM4135	oprM::Hg	Cefepime	256	64	64	64	4	0.125	0.125	≤0.06	0.125	2
PAM4756	oprM::Hg oprDd	Cefepime	256	64	64	32	2	0.125	0.125	0.125	0.125	2
PAM4135	oprM::Hg	Meropenem	64	64	64	32	4	0.03	0.03	0.03	0.03	2
PAM4756	oprM::Hg oprDd	Meropenem	256	ND	ND	64	16	0.25	0.25	0.25	0.25	2
PAM4135	oprM::Hg	Meropenem (2.5)e	32	0.5	0.125	0.03	0.03	0.03	0.03	0.015	0.03	0.5
PAM4135	oprM::Hg	Meropenem (5)e	8	0.015	0.015	0.008	0.008	0.008	0.008	0.008	0.015	≤0.125

^aThe impact of OprD inactivation on the broad-spectrum inhibitory potency of QPX7728 was evaluated based on the ability of QPX7728 to reduce the cefepime or meropenem MIC in isogenic KPC-producing strains that produced or lacked OprD. The effect of the outer membrane barrier on the broad-spectrum inhibitory potency of QPX7728 was evaluated based on the ability of the outer membrane-permeabilizing agent PMBN to increase the broad-spectrum inhibitory potency of QPX7728 in a meropenem potentiation assay using the KPC-2-producing strain of P. aeruginosa PAM4135, which lacks the MexAB-OprM efflux pump. The potency of QPX7728 was expressed as PV_max, which is the maximal potentiating value, or the concentration of the BLI that reduces the antibiotic MIC to the level seen in the parent strain that lacks KPC (corresponding to the complete inhibition of KPC).

^bAll strains produced KPC-2, the gene for which was carried by recombinant plasmid pUCP24-KPC-2.

^cCefepime and meropenem MICs in the presence of BLIs at PV_max are in boldface.

^doprD mutant PAM4756 (oprD::fs_aa126) was selected from PAM4135 on 128 μg/ml of biapenem (4× MIC).

^eMeropenem-QPX7728 checkerboard plates contained PMBN at a fixed concentration of 2.5 μg/ml or 5 μg/ml, with the PMBN concentration used being indicated in parentheses.