Relationships between Efflux Pumps and Emergence of Heteroresistance: A Comprehensive Study on the Current Findings

Table 1

HR prevalence among apparently susceptible bacteria strains and observed correlation with overexpression level EPs.

Bacteria	N	Country/isolation source	Antibiotic/heteroresistant rate (%)	Efflux pump	Ref
P. aeruginosa	131	China/clinical isolates	IMP/35.1	Increased expression of the mexE and mexY compared to their respective native ones.	[50]
	106	China/hospitalized patients	IMP/18.87	Higher mexAB expression level compared to IMP-susceptible strains.	[15]
	4	Greece/clinical isolates	IMP and MEM/-	Fourfold higher MIC compared to native cells for IMP and MEM	[51]
				Increased transcription levels of the mexB and mexY genes.
	451	China/sterile body fluids	Carbapenems/84.9	Identical PFGE profiles HR isolates with native cells	[48]
				HR isolates grew in higher MICs.
				All HR isolates are negative for MBL production.
				Upregulation in all HR, including mexB, mexC, mexE, and mexX genes.
				Reduced expression of the oprD gene in HR isolates
				Higher biofilm formation HR isolates
A. baumannii	260	South Korea/clinical isolates	TGC/52	HR isolates have eightfold-higher TGC MICs than the original isolates.	[7]
				In HR isolates adeABC efflux pumps are upregulated as a result of ISAba1 insertion into adeS genes.
	3	Portugal/MDR clinical isolates	Colistin/-	HR isolates have upregulation of adeB, adeJ, adeG, craA, amvA, abeS, and abeM Eps genes.	[14]
	576	China/clinical isolates	Colistin/1.84	Colistin HR had weaker biofilm formation capacity than the ATCC19606 strain.	[52]
				Colistin HR has upregulation of adeI and adeB genes compared to ATCC19606 strain.
K. pneumoniae	74	China/carbapenem-resistant	TGC/66.2	HR isolates have upregulation of acrB in the TGC-resistant subpopulations.	[22]
	90		PMB/100
	56		Both TGC and PMB/48.4
	393	China/clinical isolates	Eravacycline/5.08	Overexpression of oqxAB and macAB efflux pumps and the transcriptional regulator ramA.	[34]
				Overexpress acrA, acrB, and tolC genes.
				Mutations in the acrR and ramR in some HR isolates.
				oqxAB and macB mutations in some isolates.
H. influenzae	59	Switzerland/clinical isolates	IMP/77.9	Mutation in the ftsI gene (encodes PBP3).	[53]
				Mutation in the OmpP2.
				Partial deletion of acrR.
Enterobacter spp.	—	Laos and Nigeria/-	Colistin/-	Inactivation of tolC in the acrAB-tolC pump change HR to susceptible strains.	[54]
				In HR strains, overexpression of acrAB, tolC, and soxSR genes was observed.
				In addition, PAβN significantly decreases the MIC of colistin on the HR strain.

Note. N: number, Ref: reference, IMP: imipenem, MEM: meropenem, TGC: tigecycline, and PMB: polymyxin B.