Membrane Efflux Pumps of Pathogenic Vibrio Species: Comparison
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Infectious diseases caused by bacterial species of the Vibrio genus have had considerable significance upon human health for centuries. V. cholerae is the causative microbial agent of cholera, a severe ailment characterized by profuse watery diarrhea, a condition associated with epidemics, and seven great historical pandemics. V. parahaemolyticus causes wound infection and watery diarrhea, while V. vulnificus can cause wound infections and septicemia. Species of the Vibrio genus with resistance to multiple antimicrobials have been a significant health concern for several decades. Mechanisms of antimicrobial resistance machinery in Vibrio spp. include biofilm formation, drug inactivation, target protection, antimicrobial permeability reduction, and active antimicrobial efflux. Integral membrane-bound active antimicrobial efflux pump systems include primary and secondary transporters, members of which belong to closely related protein superfamilies. The RND (resistance-nodulation-division) pumps, the MFS (major facilitator superfamily) transporters, and the ABC superfamily of efflux pumps constitute significant drug transporters for investigation.

  • bacteria
  • infection
  • efflux
  • major facilitator superfamily
  • multidrug resistance
  • cholera
  • transporter

1. Vibrio Species of Human Health Significance

The Vibrio genus (Class Gammaproteobacteria, Family Vibrionaceae) is one of the most important food pathogens of human health significance in seafood. Vibrios are naturally present in freshwater, marine, and estuarine environments and are found in variable numbers in all kinds of seafood [1]. Their numbers can differ depending on several factors such as the season and physical parameters of water, such as temperature, salinity, and nutrient concentrations. Only a dozen among 100 named Vibrio species have been isolated from humans [2], representing a growing health threat to humankind. Infections due to Vibrio spp. usually ensue from exposure to contaminated water or consumption of raw or undercooked contaminated fish and shellfish [3]. However, person-to-person transmission has also been documented in Vibrio infections [1]. Vibrio infections in humans can be categorized into two groups: cholera and non-cholera infections. Vibrio cholerae causes a severe diarrheal illness, cholera, through ingestion of contaminated food or water. Non-cholera Vibrio species such as V. parahaemolyticus and V. vulnificus are widely distributed in coastal-marine waters. They can cause various infections such as gastroenteritis, wound infections, septicemia, etc., and are responsible for the majority of seafood-borne infections worldwide [4]. Cholera continues to be a gripping problem in developing countries like Asia, Africa, and Latin America but is rare in the developed world. Contrastingly, V. parahaemolyticus and V. vulnificus outbreaks are also common in developed countries.

1.1. Vibrio cholerae

The V. cholerae bacterium is the causative agent of the global disease cholera, with an estimated 1.3–4 million cases and 21,000–143,000 deaths worldwide every year [5]. V. cholerae is associated with chitinous organisms such as copepods, crustaceans, and microalgae, like zooplankton and fish [6]. V. cholerae bacteria are classified broadly as O1 and non-O1 serovars based on their observative agglutination in the presence of O1 antiserum. O1 V. cholerae and a non-O1 V. cholerae (O139 Bengal) have the potential to cause epidemic or pandemic cholera, and all other non-O1 and non-O139 V. cholerae do not infect humans or only cause mild illnesses [7]. The virulence of V. cholerae O1 and O139 Bengal is primarily due to their ability to produce cholera toxin CTX and cause epidemic diarrhea [7]. These two pandemic strains exist as natural inhabitants of aquatic ecosystems, making them facultative human pathogens. V. cholerae O1 serogroup has two biotypes (classical and El Tor) and three serotypes (Ogawa, Inaba, and Hikojima). Amongst them, the highly rampant serotype is Ogawa, whereas Hikojima is sporadic, rare, and unstable in the environment [7]. Non-O1 and non-O139 V. cholerae strains habitually inhabit rivers and estuarine areas against O1 and O139 strains. Studies have shown that non-toxigenic environmental strains could be switched to toxigenic strains through transduction with cholera toxin (CT)-encoded phage CTXϕ [8].

1.2. Vibrio parahaemolyticus

The halophilic pathogenic microorganism V. parahaemolyticus is widely distributed worldwide in coastal waters and is commonly found in seafood, sometimes in numbers as high as 103–104/g in oysters and <102/g in tropical shrimp [9]. V. parahaemolyticus is free-swimming or attached to organisms such as zooplankton, fish, shellfish, and sediment. Food-borne infections with V. parahaemolyticus occur when shellfish such as oysters and clams are consumed raw or minimally cooked. Severe watery diarrhea, abdominal cramps, vomiting, nausea, and fever are some of the symptoms of V. parahaemolyticus infection. It can also cause infections in open wounds exposed to contaminated water. However, all V. parahaemolyticus are not pathogenic, but those manufacturing either a thermostable direct hemolysin (TDH) factor or a TDH-related hemolysin (TRH) are pathogenic [10]. The TDH and TRH virulence factors are encoded by tdh and trh genes with about 70% nucleotide sequence similarity [11]. Studies have reported that <1% of V. parahaemolyticus seafood isolates are tdh+, while the incidence of trh+ V. parahaemolyticus is considerably higher, with some investigations reporting as high as 60% [9]. Since the mid-1990s, a pandemic clone of O3:K6, first detected in Calcutta, India, has been responsible for many outbreaks in Asia and the USA [12]. These strains harbor the tdh gene but not trh. V. parahaemolyticus can be isolated from farmed shrimp, and recently, early mortality syndrome (EMS) has been ascribed to V. parahaemolyticus in Litopenaeus vannamei farms [13].

1.3. Vibrio vulnificus

V. vulnificus is another important human pathogenic vibrio associated with fish and shellfish. V. vulnificus is known to cause serious infections in people with compromised immunity, liver diseases, and iron overloaded conditions, with a mortality rate as high as 30–75% [14]. V. vulnificus infections are linked with eating raw molluscan shellfish, which accumulate this pathogen from surrounding waters. V. vulnificus is responsible for about 95% of deaths associated with the consumption of seafood. V. vulnificus can cause fatal wound infections because the microorganism can enter the circulatory system and cause septicemia. Low salinities (5 to 25 ppt) and warm temperatures (20 to 35 °C) have been reported to be favorable for this organism [15][16]. Most cases of V. vulnificus infection are reported from tropical and subtropical regions. Based on their biochemical characteristics, V. vulnificus are classified into three biotypes, with Biotype 1 responsible for severe human infection and are found naturally in marine and estuarine waters, and biotype 2 are eel pathogens. Biotype 3 is a known hybrid of biotypes 1 and 2 found in freshwater fish in Israel [14].

2. Efflux Pumps and Antibiotic Resistance

The recalcitrant nature of specific toxigenic and non-toxigenic strains of Vibrio spp. can be problematic in treating severe cases of clinical infections [17]. In general, bacterial resistance to antimicrobial agents falls into several categories [18]. These microbial mechanisms include the formation of biofilms, which can permit communication between various species and, thus, facilitate the development of persister cells [19]. Biofilm communities harbor multiple microbial species enclosed within polymeric matrix systems. These biofilms are frequently associated with various surfaces and provide protection from antimicrobial agents. In many cases, microorganisms within biofilms undergo communication using quorum-sensing molecules to alter their biochemical properties. Another common mechanism of bacterial resistance involves the enzymatic alteration of drug targets, such as the ribosome or cell wall synthesizing machinery [20]. The altered bacterial targets can exhibit reduced antimicrobial drug binding affinities, preventing the growth-inhibiting properties permitting continued microbial growth. Frequently, target alterations result from spontaneous mutation and insertional mutagenesis by mobile genetic elements. Protection of the antimicrobial drug target prevents the binding to cytoplasmic cell growth machinery [21]. A well-studied target protection system involves the tetracycline ribosomal protection proteins Tet(O) and Tet(M), which are homologous to the elongation factor G (EF-G) of prokaryotic ribosomes. When bound to the 30S ribosomal subunit, Tet(O) and Tet(M) proteins remove or prevent the binding of tetracycline to the A-site of the ribosome, permitting translation to proceed unabated [22]. The enzymatic-based destruction of antimicrobial agents is an important virulence mechanism [23]. These resistance systems hydrolytically render antimicrobial agents into inactive forms. Of particular concern are the extended-spectrum β-lactamases (ESBLs) that cleave the β-lactam functional moieties of cephalosporins, penicillins, and associated β-lactam-harboring drugs. Prevention of antimicrobial permeability to the cytoplasm of bacterial cells represents a well-known drug resistance system [24]. These resistance determinants are known to reduce the expression of antimicrobial entry systems in the bacterial membrane or inactivate such drug entry proteins by mutation. Similarly, the lipopolysaccharide components of the bacterial cell wall can confer impermeability of extracellularly located antimicrobial agents. The energy-dependent efflux of multiple antimicrobial agents from bacterial cells of the Vibrio spp. is a widely recognized resistance mechanism [25][26]. These active efflux pumps can exploit the energy stored in ATP in primary active transport systems or the energy stored in ion-based electrochemical gradients in secondary active transporters. Many of these secondary active efflux pumps are called antiporters, which exchange drug and ion during transport and have multiple structurally distinct antimicrobial substrates.

2.1. General Mechanisms of Antibiotic Efflux Pumps

Inside bacterial cells of Vibrio species where the cellular targets for antimicrobial agents reside, the growth inhibitory effects of such intracellularly located drugs are diluted by various solute drug efflux systems [27]. These solute transport systems actively pump antimicrobial agents to the extracellular milieu, permitting bacteria that harbor these drug efflux pumps to grow and predominate under relatively high concentrations of structurally distinct antimicrobial agents, including those clinically relevant drugs in the chemotherapy of infectious disease [28]. Active transport of antimicrobial agents across the bacterial membranes represents a critical efflux-based mechanism for pathogen resistance to clinically relevant antibacterial agents [29].
In primary active transport systems, the energy stored in ATP is utilized by its hydrolysis to actively accumulate their water-soluble substrates on one side of the membrane [30]. Several species of the Vibrio genus harbor these primary active drug pump systems, which are described below. Another active transport system involves the biochemical modification of substrate during transport across the membrane, as exemplified by the phosphoenolpyruvate-dependent phosphotransferase system (PTS), also known as group translocation [31]. While sugar-alcohols and antimicrobial agents are included as substrates for Vibrio microorganisms [31][32][33], such active solute transport systems are utilized to enter bacterial cells.
Likewise, Vibrio species possess secondary active transport systems for drug efflux, which use the energy stored in the form of ion gradients across the membrane [34]. These ion-based electrochemical gradients, such as those involving sodium or protons, catalyze the accumulation of antimicrobial agents on one side of the membrane during a translocation process called antiport [35][36]. Together, these primary and secondary active transporters in bacteria account for a significant public health concern as mediators of potentially untreatable multidrug-resistant infectious disease-causing bacterial pathogens.

2.2. Classification of Antimicrobial Efflux Pumps

Regarding the active extrusion of antimicrobial agents, several large superfamilies of efflux pumps have been characterized in bacteria [26]. Of particular interest is the RND (resistance-nodulation-division) superfamily of drug and multidrug transporters driven by a secondary active transport mode of energization [37]. The major facilitator superfamily (MFS) is another relevant and large superfamily of transporters but is driven by passive and secondary active solute transport systems. The established multidrug and toxic compound extrusion (MATE) superfamily contains several drug efflux systems in various species of Vibrio [38][39]. Transporters of the small multidrug resistance (SMR) superfamily [40] have been classified as progenitors of the large drug metabolite transporter (DMT) superfamily [41]. More recently, transport systems that are homologous to members of the so-called proteobacterial antimicrobial compound efflux (PACE) family, such as AceI, were discovered in V. parahaemolyticus [42]. The ATP-binding cassette (ABC) superfamily harbors many members, which use ATP hydrolysis as the main mode of energy for primary active solute transport [43].

2.3. Efflux Pumps of RND Family in Vibrio Species

The resistance-nodulation-cell division (RND) superfamily of membrane transporters is composed of a tripartite system with an outer membrane protein (OMP), an inner membrane protein (IMP), and a periplasmic membrane fusion protein (MFP) [44]. Different components of the RND efflux pump are generally encoded on an operon. The proteins work in synergy to extrude a compound outside the cell, and the absence of any single protein of this tripartite system makes it dysfunctional [45]. IMP is the antiport protein energized by the protons (H+), while the MFP is an adaptor protein that connects OMP with the IMP [46][47]. As a result, the RND pump is organized into a continuous channel that allows direct exportation of the compounds from the cytoplasm to the exterior without entering the periplasmic space, thus making them a very effective drug resistance mechanism for Gram-negative bacteria [45][47][48][49]. The crystal structures AcrAB-TolC proteins of Escherichia coli [50][51] and the MexAB-OprM of Pseudomonas aeruginosa [52][53][54] have helped decipher the structure-function relationships in these RND efflux pumps [55]. RND pumps are non-specific and extrude structurally diverse and unrelated substrates across the membrane, although RND efflux pumps’ substrates are characteristically lipophilic [45][55]. Cationic, anionic, and uncharged substances and substances with multiple ionizable groups are efficiently handled by the RND pumps [45][55].
Some of the well-characterized RND efflux pumps from V. cholerae O1 include VexLM, VexIJK, VexGH, VexEF, VexCD, as well as VexAB and contribute to bile acid and antimicrobial resistance [56][57][58]. Higher expression of vexAB and vexCD genes in the presence of bile substantiates the role of these efflux pumps in bile resistance, and this might positively contribute to successful colonization of the small intestine by V. cholerae [57][58]. Genome comparison of V. cholerae O1 and non-O1 serovars revealed the presence of all but one (VexE) efflux pump in the genome of non-O1 strain PS15 [59]. The TolC OMF is essential for the functioning of most of these efflux pumps. VexAB, VexCD, and VexEF could be expressed in a hypersensitive E. coli (∆acrAB, ∆ydhE, hsd−, ∆tolC) background with the help of the TolC outer membrane factor from V. cholerae (TolCvc) [60]. Of these, VexAB and VexEF exhibited a broader substrate range that included multiple antibiotics such as erythromycin, novobiocin, and dyes and detergents, while the efflux activity of VexCD was restricted to bile acids and detergents. Apart from bile salts, certain antibiotics such as ampicillin and novobiocin have been reported as substrates for the VexH pump since the deletion of the vexH gene in a VexB-deficient V. cholerae resulted in higher susceptibility to these antibiotics [58]. VexEF is dependent on the electrochemical gradient of Na+ ions, unlike all other RND pumps energized by H+, and was the first such RND efflux pump described from bacteria [60].
No antibiotic substrates have been identified so far for VexIJK and VexLM pumps [58][60]. These efflux pumps might participate in other physiological activities essential for the survival and persistence of V. cholerae in the host and the environment. It has been shown that VexB, VexD, VexH, and VexK are necessary for intestinal colonization and production of virulence factors such as the cholera toxin (CT) and toxin co-regulated pilus (TCP) [58]. A majority of RND efflux pumps have bile acid as their substrate, and considering the importance of bile in the physiology of enteric bacteria [61], the role of these efflux pumps in the virulence gene regulation has been a topic of significant research interest. Before intestinal colonization, resistance against the toxic effect of the bile salts is accomplished by the ToxR-mediated repression of ompT, which has a negative role in bile salt resistance [62]. At the same time, ToxR activates the expression of ompU, and the OmpU-producing strains are more resistant to bile [63]. The increased efflux of bile salts follows OmpU production and transport by the RND efflux pumps. A V. cholerae mutant strain lacking all RND efflux pumps exhibited increased susceptibility to bile, decreased cholera toxin production, and an inability to colonize infant mouse small intestines [57][64]. Together, this evidence emphasizes the critical role that RND efflux pumps play in antimicrobial resistance and host persistence and virulence of V. cholerae.
The genome of V. vulnificus has 11 putative RND efflux pump-encoding genes, three of which (homologues of V. cholerae VexAB, VexCD, and AcrAB of E. coli) have been characterized by gene deletion studies [50]. A study identified the norM gene in whole-genome sequences of clinical V. vulnificus isolates [65]. While a mutant V. vulnificus lacking the vexAB homolog was more susceptible to erythromycin, acriflavine, ethidium bromide, and bile acid, deletion of acrAB homolog resulted in increased sensitivity of acriflavine alone, and vexCD deletion did not have any effect on the susceptibility to any of the antibiotics, dyes or bile acid [66]. Two TolC homologs, TolCV1 and TolCV2 in V. vulnificus, have been involved in resistance to antibiotics and inhibitory dyes. V. vulnificus mutants lacking TolCV1 and TolCV2 exhibited increased susceptibility to antibiotics novobiocin, erythromycin, and tetracycline, while TolCV1 mutant was also susceptible to DNA intercalating dyes (ethidium bromide, acriflavine) and detergents (bile acids, SDS) and exhibited reduced motility [67]. The expression of the tolCV1 and tolCV2 increased when the bacterium was exposed to antibiotics and other chemicals [66]. TolCV1 and TolCV2 could partially complement the TolC protein of E. coli by interacting with the AcrA protein of the AcrAB-TolC efflux system of E. coli [68]. Although VceC is functionally identical with the TolC and OprM outer membrane factors, they share minimal (<10%) amino acid similarity among them [69][70].
The outer membrane component TolC is generally essential for the function of RND efflux pumps irrespective of bacterial species. In certain instances, however, the TolC components of one species cannot functionally replace the TolC of the other. For example, the MICs of antibiotics for VexEF were much higher with TolC from V. cholerae (TolCvc) in an E. coli background, compared to the MICs of VexEF with TolC of E. coli (TolCEC) itself, although both share 47% identity and 7% similarity at the amino acid level [60]. Similarly, the RND efflux pumps of E. coli could not function with the TolC from V. parahaemolyticus, suggesting a species-specific preference for the TolC component [71][72]. TolC in the V. cholerae O1 El Tor strain has been reported to play an essential role in the transcription of the ToxR regulon, a finding that emphasizes the importance of efflux pump-mediated regulation of virulence in pathogenic bacteria [73].

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