Journal of Biosciences and Medicines, 2019, 7, 48-70

http://www.scirp.org/journal/jbm
ISSN Online: 2327-509X
ISSN Print: 2327-5081

Mechanisms Efflux Pumps of Acinetobacter

baumannii (MDR): Increasing Resistance
to Antibiotics

Francis T. Dongmo Temgoua, Liang Wu*

School of Medicine, Jiangsu University, Zhenjiang, China

How to cite this paper: Temgoua, F.T.D. Abstract

and Wu, L. (2019) Mechanisms Efflux Pumps
of Acinetobacter baumannii (MDR): Acinetobacter baumannii has greatly increased its degree of resistance to be-
Increasing Resistance to Antibiotics. come multidrug resistant (MDR) over the past 30 years and is on the red line
Journal of Biosciences and Medicines, 7, of the most widely replicated bacteria according to World Health Organiza-
48-70.
tion (WHO). The efflux pumps are the main cause for the increasing antibi-
https://doi.org/10.4236/jbm.2019.71006
otic resistance of A. baumannii originated from nosocomial infection. The
Received: December 12, 2018 progressive resistance of A. baumannii even on the recent drugs (tigecycline
Accepted: January 6, 2019 and fosfomycin) reduces to very effective antibiotic scale. With attention fo-
Published: January 9, 2019 cused on MDR and pan-drug-resistant (PDR) in A. baumannii multiple
works on efflux pumps chemical inhibitor (NMP, PAβN, omeprazole, vera-
Copyright © 2019 by author(s) and
Scientific Research Publishing Inc. pamil, reserpine, CCCP) are still in progress. Certain inhibitors from plants
This work is licensed under the Creative (Biricodar and timcodar, Falvone, Mahonia, Dalea versicolor, Lycopus euro-
Commons Attribution International paeus, and Rosmarinus officinalis) have the capability to have such com-
License (CC BY 4.0). pounds according to their very significant synergistic effect with antibiotics.
http://creativecommons.org/licenses/by/4.0/
In this review we focused on the growth of antibiotic resistance to explain the
Open Access
mechanism of efflux pumps into these different super families and a compre-
hensive understanding of the extrusion, regulation and physiology role of
drug efflux pumps in the essential development of anti-resistivity drugs. We
recapitulated the evolution of the work carried out in these fields during the
last years and in the course of elaboration, with the aim of increasing the
chances of decreasing bacterial resistivity to antibiotics.

Keywords
Acinetobacter baumannii, RND Efflux Pumps, Efflux Transporters, Multidrug
Resistant (MDR), Efflux Pumps Inhibitors (EPIs)

1. Introduction
Acinetobacter spp. was detected around the 20th century (1911) by famous bac-

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 F. T. D. Temgoua, L. Wu

teriologist Beijerinck [1], but it was not until 1960 that A. baumannii was de-
clared in hospital. A. baumannii belongs to the large family of non-fermentable
gram-negative bacteria capable of harming patients in surgical intensive care [2].
During the 20 past years it has developed a capital importance and its classifica-
tion among the nosocomial infections makes it a priority to all the public health
organizations considering its increase and recurrence [3]. A. baumannii is much
more present in humans and is the origins of multiple diseases like septic fever,
pneumonitis pachymeningitis and other disease [4]. Over time it has gained its
resistance through diverse modifications and is presently resistant to approx-
imately all the various groups of antibiotics even the most widely used drugs
(fluoroquinolones, macrolides, trimethoprim, b-lactams, tetracyclines, aminog-
lycosides, and chloramphenicol) [5]. The bacterial efflux operation causes the
formation of toxins and rejects antibiotics from the cells, which confers a specific
invulnerability to antibiotics. Multidrug resistant (MDR) efflux pumps are now
present in almost all microorganisms, in which bacteria is one of the main caus-
es of obstruction to action of drugs [6]; several works have concluded that MDR
is on origin of the decline progressive of drugs sensitization by bacterial muta-
tion [7] that reduces largely the valid drug for cure. However using inhibitor
components could restore bacterial susceptibility to antimicrobial agents. Efflux
pumps inhibitors’ (EPIs) synthetic or natural component is the potential drugs
for treatment of MDR or PDR A. baumannii. After describing the general me-
chanisms of efflux pumps systems in bacterial resistance, we will explain regula-
tion and physiology role of drug efflux pumps in the essential development of
anti-resistivity drugs and report the evolution of the work done during the re-
cent years especially in EPIs.

2. Mechanisms of Bacterial Resistance to Antimicrobial Agents

The bacterial resistance to antibiotics has emerged in the face of several patho-
genic agents, besides A. baumannii, albeit efforts to treat these pathogenic germs
still progressing [8]. Bacterial pathogens that have shown resistivity to a single
drug or to several agents are considered MDR bacterial. With all the efforts
united to resolve the problem via the outgrowth of new line of antibiotics, the
bacteria does not cease also to mutate quickly to acquire new mechanism of re-
sistivity or to improve their resistance to antibiotics [1] [4] [5] [9] [10] [11] [12]
[13]. Many reports showed that bacterial resistance to antibiotics is believed that
the pathogenic bacterium transfers certain genetic gene of resistance to drugs
from one species to another and automatically acquires resistant phenotypes
against the majority of the pre-existing antimicrobial agents [14]. This mechan-
ism of opposition poses a critical problem to bacterial treatments. Another sig-
nificant cause of this obstruction is the proximity of drugs to environment,
agriculture and others, leading to the emergence and development of resistances.
Clinically, a low or high or inappropriate use level of antibiotics will also imply
in the increase in bacterial resistance [15]. Presently following many research

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F. T. D. Temgoua, L. Wu

there exist different mechanisms responsible for the bacterial resistance in addi-
tion 1) modification of drug target, 2) drug inactivation by enzymes, 3) modifi-
cation of cell wall protein, and 4) activation of drug efflux system.

2.1. Alteration Drugs Target

Every drug has a specific target for destruction of bacteria, and as such when the
target is changed bacteria can easily resist to antimicrobial agents, and these have
been observed in quinolones (DNA gyrase variation or Qnr intercede purpose de-
fense), aminoglycosides (16S rRNA methylation), and β-lactams (transformation
in penicillin junction proteins). Reduced vulnerability to minocyclin and tigecyclin
occurs via transformation in gene encoding S-adenosyl-L-methionine-dependent
methyltransferase [16]. After undergone several transformation in gene lpx, pmrB
and outer membrane induce the structure of lipopolysaccharide for causing po-
lymyxin resistance [17] [18] [19].

2.2. Drug inactivation by A. baumannii Enzyme

A. baumannii synthesizes aminoglycoside-modifying enzymes well as AAD,
APH, AAC3, and AAC6' that are frequently encrypted by a quota of aba ob-
struction island-homogeneous gene cassettes including class 1 integrons [20]
[21]. A. baumannii also bring out a high quantity of antimicrobial -inactivating
enzymes, which are encoded by plasmids and chromosome for the resistance of
antibiotics developed from β-lactamine family [8]. These β-lactamases include,
enzymes from 4 class: class A (CTX-M and VEB), class B (NDM, SIM, metal-
lo-enyzmes, IMP, and VIM), class C (AmpC-type ADC enzymes) and class D or
OXA (OXA-23, OXA-51, OXA-58, and OXA-66) [22] [23] [24]. For example,
broad-spectrum TEM variants and either narrow-spectrum TEM enzymes
(ambler class A); are mutually capable to hydrolyze approximately all β-lactams.
In peculiarity, class_B and class_D as well as β-lactamas are implicated to hy-
drolyze carbapenems, a latest resort of antibiotics opposite several major patho-
gens [25] [26] [27] A. baumannii also raising the presence of some enzyme link
to the drug resistance like ADP-ribosyltransferase (rifamycin), chloramphenicol
acetyltransferase (chloramphenicol), and alteration enzyme TetX1 (tetracyclin)
[28] [29].

2.3. Modification of Cell Wall Protein: Permeableness Barrier of

OM
Target modification mechanisms, drug-specific inactivation, and efflux drugs
crossways the cell membrane barriers play an essential role in influencing the
sensitivity of Acinetobacter spp. to a wide range of antimicrobials. This trait is
due to the non-appearance of conventional high permeability trimmers (porins
of Enterobacteria spp.) [30] which has poor activity in Acinetobacter spp. and
thus belong to the minor proteins [18]. First, matching who has correctly, study
is A. baumannii and Pseudomonas aeruginosa (P. aeruginosa), OM also demon-

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 F. T. D. Temgoua, L. Wu

strate very low permeability to cephalosporin’s [17] [31] [32].

The Omp A protein monomer, the major protein of OM A. baumannii, has
been shown analytically as the main nonspecific slow porin [33] [34] which is
identical to the slow pores OprF from P. aeruginosa and OmpA from E. coli
[33]. Overexpressing OmpA gene in A baumannii would resulted in reduced
sensitivity to chloranphenicol and aztreonam (8 times decrease MIC), both of
which A. baumannii is intrinsically resistant [35] [36]; Nevertheless, there was
only a moderate (≤2 times) effect on the colistine MIC values, tigecycline, and
imipenem [37], a common antibiotics in A. baumannii infection treatment [12]
[38].

2.4. Drug Efflux Systems

During the recent years because of the poor OM absorbency drug efflux systems
has become one of the most complicated mechanisms of bacterial resistance and
has played an essential role on drug resistance specially to A. baumanii [39]. The
indulgence to amikacine and levofloxacin is the result of a negative control of
the gene and protein CarO 31 - 36 kDa [10] and up regulation of 14 genes at OM
by varying the amount of physiological NaCl.

3. MDR Efflux Pumps: Structure and Regulation

The structure of the efflux system is comprised of 3 well-defined parts each
playing a function in the drug efflux mechanism, including the outer membrane
(OM) [40], the internal membrane (IM) and the fusion protein at the interme-
diate level (MFP); Each part of the structure EP has a certain factor causing re-
sistance to approximately every groups of antibacterial [41] [42]. In reference to
further research, it has been proven that there are five different families of efflux
pumps present on A. baumannii:
• major facilitation super family (MFS);
• multidrug toxic composite extrusion (MATE) transporters;
• resistance nodulation-division (RND) super family;
• ATP binding cassette (ABC) transporters;
• small multidrug resistance (SMR) family.
Recently other studies have reported a sixth efflux family named PACE (pro-
teobacterial antimicrobial composite efflux) present in the A. baumannii [43].
However, because of inadequate data, we will concentrate much more on the
first 5 families present in Figure 1 where a totally understanding of structure
and regulation is not complete.

3.1. RND Efflux Pumps

The large family RND efflux is special of the rather complex compared to other
family. it is very represented and has a special role in almost all major gram-negative
bacteria and developing multiple resistance to antibiotic also call MDR such as A.
baumannii, E. coli, and P. aeruginosa [46]. RND efflux on A. baumannii has

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F. T. D. Temgoua, L. Wu

Figure 1. Structure of major families A. baumannii efflux pumps + PACE family a newly superfamily identify (adapted from [44]
and [45]).

mainly three gene (adeABC, adeIJK, adeFGH) and some special gene (adeDE,
adeAA) [47].

3.2. adeABC
The adeABC operon was newly discovered on the antibacterial agents of fluoro-
quinolones and aminoglycosides in the efflux system RND and divided into 3
part: adeB on inner membrane efflux transporters, adeA on membrane fusion
proteins, and adeC on external membrane proteins [48]. AdeB has the largest
representation on A. baumannii strains (80%), adeA and adeC has 42%, and 40%
respectively [49]. The gene adeABC have almost the same structure that genes
MexAB-OprM for P. aeruginosa and genes AcrAB-TolC for E. coli [48] [50].
Because of this high proportion of adeB gene compare to the others, its inactiva-
tion would dramatically cause sensitization to antimicrobial drugs in the hospital
for A. baumannii [51]. The increasing concentration of MIC would be beneficial
to important drug classes like aminoglycosides, tetracyclines-tigecycline,
β-lactams, fluoroquinolones, macrolides, trimethoprim, and chloramphenicol
[52]. Despite the advancement of research, rifampicin, flusidic acid and some-
times colistin remain resistant to isolate A. baumannii. Single last chances of
fight against A. baumannii isolates are tigecycline but show a hard resistance to
adeABC and also it presents a high resistance efflux. The MIC levels of tigecyc-
line remain a clinical problem [42] [53]. Remarkably, about 20% of adeC was
found to be involved in tigecycline resistance tests in A. baumannii demonstrating
that in the adeABC gene, adeAB can keep walking without adeC except on [54].
The adeC plays a much more an almost negligible role in RND efflux system.
The two components adeR and adeS are responsible for the regulation of the
expression system of adeABC [55]. They are also called protein kinases and are
found on both sides of adeABC in different trajectory. AdeRS, plays a determin-

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 F. T. D. Temgoua, L. Wu

ing role in increasing resistance of adeABC. Some result shows that a dysfunc-
tion of adeR and or adeS will increase the resistance of tigecyclin, chlorampheni-
col, minocyline, erythromycine, cefotaxime, tetracycline, fluoroquinolones, and
trimethoprim [19] [32]; as well increase the sensitization of amino-glycosides of A.
baumannii isolate. Recently an intense sight of carbapenem resistance was dis-
covered in A. baumannii isolate from the adeABC system such as class D carba-
penemases, meropenem, and imipenem, and it remains a serious concern in
clinical therapy [13] [56]. The ISAba1 insertion produced by the adeS mutation
confers resistance over expression to tegecycline.

3.3. adeIJK
The second largest pump of the RND family’s adeIJK also comprises of adeI,
adeJ, adeK genes which occur on the three parts of the pump efflux structure
respectively. AdeIJK was described initially in the years 2008 [5] [26] with the A.
baumannii clinical strains fluctuating between 86% and 100% in a presence of
the predominant gene adeJ. With various reported a MIC dimness of adeIJK
mainly the resistance of A. baumannii to β-lactamines, lincosamides, fluoroqui-
nolones, chloramphenicol, trimethoprime, and fusidic acid has been noticed
[57]. The selection of the majority gene adeJ, will lead to an amplification in the
sensitivity of chloramphenicol, macrolides, lincosamides, tetracyclines and qui-
nolones and β-lactams [58] [59]. The regulation of adeIJK is less complex than
that of adeABC, but at about 750 - 850 kbp of adeIJK operon there is a regulator
adeN belonging to the class of tetR [35]. The presence of this regulator adeN and
mutation in different media led to an increase the resistance to antimicrobial
drugs (ertapenem, aztreonam, tigecycline, meropenem, and minocycline) in A.
baumannii [47]. Several studies have shown that the threshold of expression of
adeIJK is lower than that of ABC, which indicated that the level of toxicity of
adeIJK in the patient is well regulated [48] [52] [60]. It has been detected that
adeIJK and adeABC have some similarity as the efflux of the same antibacterial
drugs (fluoroquinolones, tetracyclines and chloramphenicol) [52] from A. bau-
mannii and properties comparable to P. aeruginosa mexAB-OprM. Studies on
production and regulation adeABC and adeIJK resulted in the formation of bio-
films [36].

3.4. adeFGH
Outstanding variation of adeABC and adeIJK, has induced the discovery of
adeFGH operon sometime after adeIJK identification. The presence of adeFGH
in the genus A. baumannii through exposure to certain antibacterial agents (nor-
floxacin) [22] [61] and is also a true source of multidrug. The genes of the
adeFGH operon, the adeG is the most representative of more than 80% of the
others [37]. AdeFGH has also become popular in the species of A. baumannii
due to its severe resistance to fluoro-quinolones, tetracyclines, tigecycline, chlo-
ramphenicol, trimethoprim, sulfamethoxazole and moderate resistance to eryt-

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F. T. D. Temgoua, L. Wu

hromycin, rifampicin and aminoglycosides, [61] and also β-lactams. AdeFGH is

regulated by LysR (LTTR), also called adeL. The adeL mutation will conduct to
the adeFGH level rise. adeXYZ has also been found in A. baumannii genospecies
3 and has the same structure and positioning of MFP, OM, IM with propositions
80% (adeX), 89% (adeY) and 87% (adeZ) [39] [62] [63]. AdeXYZ and adeDE are
also regularly present in A. baumannii GDG3 as opposed to GDG2 for ade IJK
and adeABC. The engagement of adeXYZ in the resistance mechanism is not en-
tirely described. Some research showed that the suppression or perturbation of
adeFGH or of another in the RND system does not greatly modify the sensitivity
to the antibiotics [2] [64].
It has been found that the A. baumannii (GDG3) gene and specific resistance
to certain antibiotics (ceftazidime, tetracycline, amikacin, ciprofloxacin, eryt-
hromycin, rifampin, meropenem, chloramphenicol) [16] [26], is due to adeDE
gene in A. baumannii chromosome, and have resistance to imipenem. Unlike to
other efflux system (adeABC, adeIJK), the adeDE gene does not have an outer
membrane [27] [32]. Previous studies have demonstrated inconsistency between
adeDE and adeABC-adeIJK due to the presence of adeABC-adeIJK/inter
1-negative adeS in some isolates for the detection of adeE [65].

3.5. MFS Efflux Pumps

MFS is the subsequent most studied efflux mechanism in species A. baumannii
have identified some genes cmlA, tet(A/B), craA, and floR as the most present
and appertain to the superfamily MFS [66]. Plural research has explained a par-
ticularity of resistance caused by tetA and tetB [61]. These two genes are not in-
volved in resistance to tigecycline, yet tetA leads to a tetracycline resistance while
tetB induce the resistance to tetracyclin and minocyclin [67]. In A. baumannii
isolate resistant to tetracycline, the overexpression rate of tetA is 30% - 45%
whereas tetB is 32% - 72% [29] [67]. The cmlA gene of MFS is resistant to cer-
tain β-lactams, chloramphenicole, fluoroquinolones, tetracycline and rifampicin.
craA is particularly resistant to chloranphenicol, imipenems, quinolones, ami-
noglycosides, and tetracyclines [68]. The MFS energy source is proton motive
force (H+) facilitating H+ motive force inhibition to increase the sensitization of
antimicrobial drugs [69]. Horizontal transmission was discovered by the associ-
ation of two tetB-tetR genes in plasmid and the ISCR2 element of the MDR iso-
late. It has been reported that floR gene and cmlA gene were associate with abaR
gene in A. baumannii chromosome [70] [71] [72].

3.6. MATE Efflux Pumps

The first and most frequent gene of the MATE family present in A. baumannii is
the adeM gene. It represents between 63% - 100% in MDR of A. baumannii [26]
[71]. AdeM protein contains about 447 amino acids and multiform hydrophobic
regions. The antimicrobial drugs resistant due to adeM gene are not related to
adeABC and totally known. In certain studies it was noted that adeM is not as-

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 F. T. D. Temgoua, L. Wu

sociated with the resistance of β-lactams, or cephalosporin [73] [74]. But it could
have an implication of resistance in that of amino glycosides, trimethoprim, flu-
oroquinolones, erythrocin, and chloramphenicol. The MATE family is powered
by double reservoir of energy PMF (motive force of the proton) and sodium ion
gradient Na+ [75]. This high energy source could be a particular reasons why
adeM gene is seen as an important target for elaboration of efflux pumps inhibi-
tory antibiotics that could help restores A. baumannii sensitization [76] [77].
The recapitulate of Efflux pumps family in A. baumannii and Antimicrobial
drug target was listed in Table 1.

3.7. SMR Efflux Pumps

AdeS gene was characterized in 2009 initially in the efflux pump system by in-
creasing the MIC (5 - 6 times) on an E. coli strain for the resistance of novobi-
ocin and erythromycin. AdeS gene is the main efflux pump of SMR family

Table 1. Efflux pumps families in A. baumannii and antimicrobial drug.

Efflux pumps Efflux pumps genes Energy

Substrates
families and (regulators) resource

RND adeABC Proton motive Aminoglycosides, Benzalkonium Chloride, Β-Lactams, Tetracycline, Chloramphenicol,
(adeSR, baeSR) force (H+) Deoxycholate, Ethidium Bromide, Erythromycin, Tigecycline Fluoroquinolones, Nalidixic
Acid, Methyl Viologen, Sodium Dodecyl Sulfate.

adeAA2B (baeSR) Tigecycline

adeFGH (adeL) Sodium Dodecyl Sulfate, Tetracycline, Tigecycline, Nalidixic Acid, Sulfonamides, Ethidium
Bromide, Fluoroquinolones, Erythromycin.

adeIJK (adeN, Azithromycin, Benzalkonium Chloride, Β-Lactams, Farnesol, Chloramphenicol,

baeSR) Clindamycin, Crystal Violet, Deoxycholate, Fusidic Acid, Erythromycin, Fluoroquinolones,
Minocycline, Nalidixic Acid, Rifampicin, Sodium Dodecyl Sulfate, Triclosan,
Tetraphenylphosphonium, Trimethoprim, Tetracycline.

MFS craA Proton motive Chloramphenicol

force (H+)
cmlA Chloramphenicol

floR Chloramphenicol, Florfenicol

tetA(B) (tetR) Tetracycline

MATE abe M Proton motive Acrifl Avine, 6-Diamidine-2-Phenylindole, Daunomycin, Doxorubicin, Fluoroquinolones,
force (Na+/H+) Gentamicin, Rhodamine 6G, Tetracycline.

SMR abeS Proton motive Acridine Orange, Acrifl Avine, Benzalkonium Chloride, Β-Lactams, Chloramphenicol,
force (H+) Ciprofl Oxacin, Deoxycholate, Ethidium Bromide, Tetraphenylphosphonium,
Erythromycin, Novobiocin, Sodium Dodecyl Sulfate,

Smr (A1S_0710) Deoxycholate, Sodium Dodecyl Sulfate

ABC macAB-tolC (baeSR) ATP hydrolysis Erythromycin, Gramicidin

(P-gp)

PACE aceI Proton motive Chlorhexidine

force (H+)

Acinetobacter Genospecies 3

RND adeDE Proton motive Ceftazidime, Amikacin, Ciprofloxacin, Chloramphenicol, Erythromycin, Ethidium
force (H+) Bromide, Meropenem, Rifomycin, Tetracycline

RND adeXYZ Β-Lactams, Ciprofloxacin, Tetracycline, Rifampin, Chloramphenicol

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F. T. D. Temgoua, L. Wu

present in A. baumannii. This gene adeS belongs to a particular resistance for

fluoroquinolones, novobiocin, erythromycin, detergents (benzalkonium chlo-
ride), chloramphenicol, and dyes [8] [21] [49]. AdeS is identical at 52% to emrE
(E. coli) found in the genome A. baumannii genome. AdeS is composed of about
108 acid amines. Because of its constant need for energy (H+), the suppression of
this energetic source would restore susceptibility to drugs on MDR A. bauman-
nii [70] [78] [79].

3.8. ABC Efflux Pumps

ATP binding cassette (ABC) of super family efflux pumps are recognized to be
censurable for multidrug-resistance due of P-glycoprotein (ABCB1) [80]. ABC
proteins are including in the cytoplasm (inner) membrane of germ, and mem-
branes in eukaryotes. In the human body, ABC proteins encodes for 49 proteins, a
particular fraction has been distinguished in function and biochemistry terms to
others [39] [81]. They have been organized into 7 sub-families established on phy-
lo-genetic examination. P-glycoprotein (ABCB1) contains 170 kDa trans-membrane
glycoprotein and practically the most at largely studied transporters that pro-
mote cancer cells to develop drug resistance. Unlike the other family of efflux
pumps, ABC family is powered by hydrolysis energy sources of ATP (ADP + Pi)
which gives cellular resistance to large number of drug molecules [82] [83]. The
ABC proteins functionally contain two areas for substrate transport and 2 areas
of NBD (nucleotide binding) with ATP hydrolyse in the process. ABC family is
recognized in A. baumannii to have resistance to erythromycin and gramicidin,
but it is very present on cancer cells [30].

3.9. PACE Efflux Pumps

The proteo-bacterial antimicrobial compound efflux family (PACE) is uncom-
mon of the newest families of efflux pumps identified in the latest 15 years [84].
PACE family described on plural gram-negative bacteria like E. coli, K. pneu-
moniae, Vibrio parahaemolyticus, Salmonella enterica, P. aeruginosa, Entero-
bactre cloacae, and serovar Typhi [36] [43] [85]. Its homologous aceI gene found
to be resistant to chlorhexidine and its overexpression also lead to resistance to
dequalinium, benzalkonium chloride, and acriflavine. In A. baumannii, aceI also
induces the resistance of chlorhexidine and oxidants [85]. The aceI gene of
PACE family could be the 6th group of MDR efflux pumps [44].

3.10. Mechanisms of Transporters in the Efflux Pump Systems

According to structural and bioenergetics characteristics, carriers could be sepa-
rated into two major groups [80] [86], 1) transporters that hydrolyze ATP as an
energy source; they are also summons ABC transporters (ATP binding cassette)
[81], and 2) transporters that use the proton H+ (and/or Na+ sodium MATE
family) for energy source [81]. Transporter of proton is the main common con-
veyance present in gram-negative bacteria especially in multidrug resistant. The

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 F. T. D. Temgoua, L. Wu

mechanisms of transporter expression and regulation in bacterial present a

complex structure with different variable which are still understudy [53] [87].
The First Transporters: ATP binding cassette Transporters. The mamma-
lian P-glycoprotein (P-gp, MDR1) is one of the particularly studied ABC trans-
porters, and their utilization in chemotherapy has shown that their expression
confers resistance to cytotoxic compounds [88]. Ubiquitous ABC transporters
have many different functions in transport including drugs, metabolites and the
flow of toxins [89]. ABC transporters particularly constitutes, of two hydro-
phobic transmembrane domains and two cytoplasmic domains which binding
ATP [90].
The Second Transporters in MDR bacterial efflux pumps system are
represented in four families: RND, MFS, MATE, and SMR family [81] [89]. The
MFS protein have 12 or 14 transmembrane segments (TMS) coming from two
separate congregate and they are also responsible for transport of drugs, sugars,
and intermediate metabolites [66]. Membrane proteins of the SMR family are
engaged in the activity of lipophilic cationic drugs in A. baumannii [91]. These
are the slightest known drug efflux proteins, with just 4 TMS predicted. They
can function as either hetero- or homo-oligomeric complexes. Unlike pumps
MFS families, RND and SMR, which act as anti-proton/anti-drug, the 12-TMS
collapse pumps MATE family afresh recognize [108] are mainly anti-drugs Na+
[90]. RND efflux systems presented a 3D structure of proteins of tripartite which
is not totally understood by the configuration of these systems [26] [60]. It was
also noted that RND pumps of A. baumannii and gram-negative a tripartite sys-
tem. RND efflux protein are combined of 12 TMS including 2 large periplasmic
which provide specify substrate [92] [93].

4. Mechanisms of Efflux Pumps Inhibitors (EPI)

In fighting bacterial resistance which has increased, it would be useful to employ
inhibitors of resistance efflux pumps to restore the fundamental action of antibi-
otic. Efflux pumps are the newest bacterial resistance mechanism allowing resis-
tance to almost all antibiotics [94]. Some molecules (chemical or natural) have
the capacity to act specifically on the efflux system to restore the action of anti-
biotics and commonly called efflux pumps inhibitors (EPIs) [95]. In the A. bau-
mannii species several chemical inhibitors have already been tested [96]. Only
certain inhibitor has shown conclusive results but remains difficult to apply in
clinical due to high levels of toxicity for the human organism [97] [98]. To dis-
cover adequate EPI, different strategies can be considered depending on the
cause gene or the level of cellular resistance [99]. Given the enormous variety of
drugs, it would be cost-effective and economical to focus more on the classes of
antibiotics that could have a serious impact on A. baumannii with respect to
pharmacokinetics and toxicity. Finally, the screening of banks or chemical
compounds emitted by biodiversity may allow the identification of performing
compounds, which could be further enhanced by experiments with struc-

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F. T. D. Temgoua, L. Wu

ture-activity relationships [100]. The mechanisms implicated in inhibition of ef-

flux pump systems are not clearly understood [6] [101] but it has been suggested
that inhibition of efflux pump performance in A. baumannii may be completed
by different channel, Figure 2 present the various target of EPI such as 1)
Change regulatory steps of efflux pumps expression; 2) Inhibit the practical con-
struction of the multi-component pump; 3) Obstruct the outer membrane ways
(adeC, adeK) with a plug; 4) Disintegrate the energy resource of efflux, di-
rect-specific or indirect-general via a destruction of energy mechanisms of the
bacterial transporters; 5) Apply a non-antibiotic molecule to the affinity sites of
the efflux pump for competitive or no inhibition; 6) Modify the chemical struc-
ture of useful antibiotics in order to reduce its relationship for efflux identifica-
tion and limiting sites or to obstruct the efflux transport.
PAβN and 1-(1-naphthylmethyl)-piperazine (NMP) are commonly used for
the mechanism of inhibition efflux pump, they were tested in combination with
different antimicrobial drugs facing A. baumannii [96] [102]. At MIC values ≥
400 μg/ml (PAβN) and 200 ≥ 400 μg/ml (NMP) we observed intense antibacteri-
al activity in the behavior of these two agents. The work done by Pannek S et al.
on these two EPI reveals a reversal of the resistance phenotype or a limitation in
the sensitization of bacterial cells with a low concentration at 25 μg/ml [101].
When MIC decrease eight-fold some antimicrobial drugs like levofloxacin,
chloramphenicol, linezolid, ciprofloxacin, clarithromycin, tetracycline, and ri-
fampicin, restores sensitivity to drugs with a density 100 μg/ml of the two EPIs,

Figure 2. Various targets for inhibition of complex efflux pump (adapted from [6] and [102]).

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 F. T. D. Temgoua, L. Wu

which means that one or both EPIs have a affirmative effect [55] [103]. It was
also noticed that PAβN and NMP, either at 100 μg/ml, restored the susceptibility
on tigecycline (double-reduction of MIC) and fluoroquinolone (decrease MIC 2
- 16 times) [104] [105].
In other studies, PAβN at 10 μg/ml decreased predominantly MIC concentra-
tions of trimethoprim, clindamycin and chloramphenicol [97] [102]. Twice a
time on clinical isolates, whereas PAβN at 20 μg/ml reduced nicidixic acid MIC
to 16-fold but showed little effect on sensitiveness to ciprofloxacin [106]. At 100
μg/ml PAβN are also sensible minocycline activity by decreasing ≥ 04-fold MIC
values [107]. Delightful, one study has propose a contradictory effect of NMP at
64 μg/ml on susceptibility to tetracyclines (i.e., increased susceptibility to mino-
cycline, tetracycline, doxycycline) and tigecycline (reduced susceptibility) [107]
[108] [109]. Presumably, the EPIs have powerful effect on resistivity reversal
with molecules that have relatively acute MIC values such as clindamycin, chlo-
ramphenicol, linezolid rifampicin, trimethoprim clarithromycin [107] [108]
[110]. Moreover, another study also examine the effect of phenothiazines, ome-
prazole (prochlorperazine, chlorpromazine, and promazine), verapamil and re-
serpine, on susceptibility cells with phenothiazines being the only emissary ca-
pable to re-establish sensibility to some antibiotics (≥8 time MIC decrease) [97]
[109].
Recently some research demontrated the collision on colistin susceptibility of
colistin-susceptible and colistin-resistant bacteria gram(-) including A. bauman-
nii by using the effect of CCCP (carbonyl cyanide m-chlorophenyl hydrazone),
NMP, PAβN, omeprazole, verapamil, reserpine [108] [111]. The expression sta-
tus of any drug efflux pump was not evaluate, and only carbonyl-cyanide m
-chlorophenyl hydrazone (CCCP) was reveal to particularly offers influence on
reversing colistine resistant for A. baumannii. Nevertheless, proton channel
suchlike CCCP act on dislocation of proton motive energy crossways the cytop-
lasm membrane and do not active on pump perse [111]. Efficacy of EPI car-
bonyl-cyanide m-chlorophenyl hydrazone (CCCP) on colistin resistance is exot-
ics [98] [108]. Serum agents, N-tert-butyl-2-(1-tert-butyltetrazol-5-yl) sulfany-
lacetamide and (E)-4-(4-chlorobenzylidene) amino) benzenesulfonamide were
combined to find accumulation and potentiating the improvement of the mino-
cycline activity of several antimicrobials opposite A. baumannii [73] [74].
The perfect results of EPIs could stimulate the action of new antimicrobial
drugs. The compound, 3-(phenylsulfonyl)-2-pyrazinecarbonitrile, is an agent
developed fronting resistant nosocomial pathogens [112] [113]. The combine of
PAβN can decrease this MIC value by four time of A. baumannii at MIC is 64
μg/ml [97] [102]. Another lately kibdelomycin natural antibiotic was found, ex-
hibits a broad-spectrum effect with the MIC 90 value of 0.125 facing A. bau-
mannii [112], this agent appears to be a distressed substratum of efflux pumps.
Finally, any agents that can traverse the OM of A. baumannii are expected to
counter the activity of the efflux pumps in augmentation the drug ingress to
their targets [114] [115].

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F. T. D. Temgoua, L. Wu

In this regard, many plant extracts of EPI (in addition steroidal alkaloids con-
essine) are clever to break down the OM barrier to exert a synergistic efficacy on
the amelioration of the activity of divers antimicrobials facing A. baumannii
[116] [117] [118]. Natural efflux pump inhibitors (plant extracts): Biricodar and
timcodar, Falvone, Berberis, Mahonia, Dalea versicolor, Lycopus europaeus,
Rosmarinus officinalis, are the most common use against bacteria [116]. The
analytical results of the natural inhibitor Rosmarinus officinalis and Lycopus
europaeus have shown great efficacy on efflux pumps to restore the sensitivity of
antibiotics against MDR strains of A. baumannii and P. aeruginosa [119]. The
natural extract Geranium coespitosum, Punica granatum and Euphorbiaceae can
inhibit the potentiating activity of strains MDR Staphylococcus aureus to restore
the sensibility of erythromycin, fluoroquinolone, gentamicin, ampicillin, tetra-
cycline, chloramphenicol [120] [121]. Extracts of Berberis aetnensis coming
from volcano region can reduce the resistance of ciprofloxacin for P. aeruginosa,
S. aureus, and E. coli [122] [123]. The natural inhibitors Mellisa officinalis,
Daucus carota, Levisticum officinale, Glycyrrhiza glabra, has demonstrated a
great activity facing S. tyhimuriun and K. pneumoniae by restore the sensibility
of tetracycline, chloramphenicol and fluoroquinolones [94] [95].

5. Conclusion
Drug efflux mechanisms are serious global problems for the fight of nosocomial
infections including A. baumannii in clinic. RND families are the greatly com-
plex and resist numerous types of antimicrobial drugs. Despite of the develop-
ment and use of chemical molecules (NMP, PAβN, omeprazole, verapamil, re-
serpine, CCCP) as an EP inhibitor, many research having present results that are
approximately conclusive in vitro always face elevated degree of toxicity to the
physical body if it is applied in clinic. Hence the importance for future research
focuses more on natural inhibitor extract from plants (Berberis, Mahonia, Dalea
versicolor, Lycopus europaeus, Rosmarinus officinalis). The development of
these new type inhibitors could constitute a better and effective voice to resolve
definitively the bacterial MDR problem (including A. baumannii). Therefore,
control pharmacokinetic, pharmaco-dynamic complete and combined will give
high efficacy and acceptable degree of toxicity.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this pa-
per.

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