Clinical Status of Efflux Resistance Mechanisms in Gram-Negative Bacteria

Abstract

Antibiotic efflux is a mechanism that is well-documented in the phenotype of multidrug resistance in bacteria. Efflux is considered as an early facilitating mechanism in the bacterial adaptation face to the concentration of antibiotics at the infectious site, which is involved in the acquirement of complementary efficient mechanisms, such as enzymatic resistance or target mutation. Various efflux pumps have been described in the Gram-negative bacteria most often encountered in infectious diseases and, in healthcare-associated infections. Some are more often involved than others and expel virtually all families of antibiotics and antibacterials. Numerous studies report the contribution of these pumps in resistant strains previously identified from their phenotypes. The authors characterize the pumps involved, the facilitating antibiotics and those mainly concerned by the efflux. However, today no study describes a process for the real-time quantification of efflux in resistant clinical strains. It is currently necessary to have at hospital level a reliable and easy method to quantify the efflux in routine and contribute to a rational choice of antibiotics. This review provides a recent overview of the prevalence of the main efflux pumps observed in clinical practice and provides an idea of the prevalence of this mechanism in the multidrug resistant Gram-negative bacteria. The development of a routine diagnostic tool is now an emergency need for the proper application of current recommendations regarding a rational use of antibiotics.

Targeting the Holy Triangle of Quorum Sensing, Biofilm Formation, and Antibiotic Resistance in Pathogenic Bacteria

“…Besides being induced by antibiotics and various other toxic compounds for the bacteria, the expression of the efflux pump is regulated by QS (see Section 3), various stress stimuli (e.g., membrane disruption, protein misfolding), changes in metabolic state, and when the bacteria are embedded in a biofilm (see Section 4) [31,64,77,216]. Moreover, additional factors can result in the constitutive overexpression of efflux pumps, including (i) mutations in the local repressor gene; (ii) mutations in a global regulatory gene; (iii) mutations in the promoter region of the efflux gene; (iv) insertion elements upstream of the efflux pump gene [164,165].…”

“…These efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM) have overlapping spectra of antibiotic substrates and confer resistance to carbapenems, fluoroquinolones, and/or aminoglycosides [25]. The MexAB and MexCD are located in the inner membrane, while the OprM and OprJ are in the outer membrane [64]. The mexAB-oprM operon is repressed by MexR [196] and NalD [229], while activated by BrlR [230] and CpxR [231] (Figure 6).…”

Effects of Lysine N-ζ-Methylation in Ultrashort Tetrabasic Lipopeptides (UTBLPs) on the Potentiation of Rifampicin, Novobiocin, and Niclosamide in Gram-Negative Bacteria

“…NIC was selected because it has been shown to synergize with polymyxins and overcome polymyxin resistance in polymyxin-resistant GNB [28]. Chloramphenicol (CHL) was selected as an antibiotic that is greatly affected by efflux [29]. The combination studies were performed by fixing the concentration of the UTBLPs to 6 µM, which is below 1 4 MIC required for synergistic activity.…”

Evasion of Antimicrobial Activity in Acinetobacter baumannii by Target Site Modifications: An Effective Resistance Mechanism

“…TetA can act synergistically with efflux pumps belonging to another superfamily called RND. Three systems, AdeABC, AdeFGH:RND, and AdeIJK, function as mechanisms of resistance to tigecycline; the expression of the latter two systems is controlled by AdeL, a LysR-type transcriptional regulator, and AdeN, which is a TetR-type transcriptional regulator [ 19 , 81 , 82 , 83 , 84 ].…”

“…AdeABC is also associated with aminoglycoside resistance. Several studies have detected the presence of adeA and adeS genes in a frequency of more than 60%, and that the percentage may vary due to the pattern of antibiotics used, the type and number of clinical samples analyzed, methodology used, and environmental factors, among others [ 19 , 59 , 60 , 83 ].…”