Abstract
Antimicrobial resistance (AMR) represents a major challenge to global health. This problem is most apparent in healthcare facilities, with a comparatively small number of pathogens being responsible for a substantial burden of hospital acquired infections globally. One of the key pathogens is the Gram-negative coccobacilli, Acinetobacter baumannii. It has been estimated that between 47% and 93% of A. baumannii infections are associated with multi-drug resistance (MDR), which is facilitated through a variety of well documented mechanisms (β-lactamases, efflux pumps, aminoglycoside-modifying enzymes, permeability defects, and target modifications). As our current pool of antimicrobial treatments becomes increasingly less effective, it is vital to identify new targets that can aid in the development novel treatments and strategies. In this we review we outline the key virulence mechanisms in A. baumannii (gene acquisition and adaptation, resistance to stresses, biofilm formation, and host interaction) and discuss their potential as targets for new therapeutics to reduce the impact of infections caused by MDR A. baumannii.
Keywords
Introduction
One of the greatest challenges currently facing modern medicine is the emergence and dissemination of antimicrobial resistance (AMR) in bacterial pathogens. This problem has been eluded too by multiple international organisations, with the American CDC identifying a group of bacteria associated with increasing health concerns in relation to AMR and naming them the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).
1
These organisms are responsible for a substantial burden of hospital acquired infections globally, and possess the ability to “escape” the vast majority of antimicrobial treatments.1
Among the most concerning of the ESKAPE pathogens is the bacterium Acinetobacter baumannii (A. baumannii) which in 2017 was, alongside Pseudomonas aeruginosa and some Enterobacteriaceae, identified as a priority 1 pathogen for the development of new antimicrobials by the World Health Organisation (WHO).2
WHO. WHO publishes list of bacteria for which new antibiotics are urgently needed Geneva2017 [Available from: https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed.
Acinetobacter spp. are Gram negative coccobacilli, they are strictly aerobic and non-motile, and can be found in a variety of environments including soil and water.
3
,4
A. baumannii and the wider Acinetobacter calcoaceticus-baumannii (Acb) complex, form a distinct monophyletic clade within the Acinetobacter genus, and can be distinguished by the acquisition of various virulence factors that have helped contribute to their widespread prevalence and large disease burden.5
These virulence factors include structures that facilitate persistence of the organisms on abiotic surfaces, the production of unique siderophores to sequester iron, and features allowing for the development and maintenance of AMR.5
It is estimated that infections with A. baumannii account for 0.7–4.6% of all healthcare related infections by Gram negative bacilli, with rates of multi-drug resistance (MDR) ranging from 47% to 93% according to a 2016 study published as a component of the SMART surveillance initiative.
6
The clinical manifestations of A. baumannii infection vary greatly and include pneumonia, bloodstream infections, urinary tract infections (UTIs), meningitis, and infections of traumatic wounds.7
The outcomes of these manifestations are commonly dependent on the susceptibility of the causal organisms to various antimicrobial treatments.7
While A. baumannii was historically susceptible to a wide range of antimicrobials, in recent decades widespread MDR phenotypes have become a serious problem in healthcare facilities; now clinical A. baumannii are commonly resistant to a range of β-lactams, aminoglycosides, fluoroquinolones, and even the last resort antimicrobial, colistin.8
The various mechanisms of AMR in A. baumannii are well described and associated with β-lactamases, efflux pumps, aminoglycoside-modifying enzymes, permeability defects, and target modification.8
, 9
, 10
As our current arsenal of antimicrobials is become increasingly less effective at treating A. baumannii infections, there is mounting pressure to find new targets for novel treatments to address the problem of an untreatable bacterial infection. Here, in this review we assess the bacteriology of A. baumannii with a focus the ability of the organism to function as a pathogen, using these insights we discuss some potential approaches for novel therapeutics.
Gene acquisition and adaptation
One of the major aspects facilitating A. baumannii in becoming a successful pathogen and major sink/source of AMR mechanisms, is its ability to adapt rapidly through traditional selection and its highly competent nature when incorporating foreign DNA.
10
The spontaneous mutation rate in MDR A. baumannii has been estimated to be up to 2.1 × 10−6 mutations per cell division, and several variants with hypermutator phenotypes have been described.11
Hypermutator variants arise at comparatively low, yet appreciable frequencies in clinical isolates and have altered protein expression, including upregulated serine protease activity and downregulated polyisoprenoid-binding and peptidoglycan-binding protein.11
This phenotype has been found to arise independently during antimicrobial treatment through the inactivation of mutS, which encodes a protein that is integral to the DNA repair pathway.12
Mutations that inactivate mutS as well as mutL, encoding for a protein that provides stability for MutS during mismatch repair, are primarily frameshift point mutations that principally affect the C-terminus of MutS preventing ATP binding and hydrolysis, and the C-terminus of MutL inhibiting dimerization.13
These point mutations, given their appreciable frequency in clinical isolates, would be difficult to prevent with therapeutics; therefore, it is important that any new therapies have low endogenous resistance potential.13
,14
While this may seem obvious, it is worth stressing that any target that can be altered quickly would limit the longevity of any new potential treatment.Aside from the ability to generate spontaneous mutations, the other major method(s) A. baumannii exploits to develop AMR is the acquisition and incorporation of foreign genetic material. AMR genes can be transported on a wide variety of mobile genetics elements (MGE) including integrons, transposons, resistance islands, and insertion sequences via horizontal gene transfer.
15
,16
This access to a large reservoir of foreign genetic material induces broad genetic diversity and is one of the major contributing factors explaining why A. baumannii has become widely resistant to antimicrobials. The impact of MGE facilitating AMR in A. baumannii is further compounded by two additional factors associated with the environment in which it commonly circulates. First, A.baumannii has been shown to be naturally competent in some circumstances and has the ability to acquire genes from other species. This phenomenon may be particularly dynamic and common when A. baumannii can share the same habitat as organisms such as Klebsiella pneumoniae.16
Secondly, exposure to human fluids may also impact on exogenous DNA-acquisition in A. baumannii.17
Human plural fluid has been shown to induce competence-associated gene expression and transformation frequency; additionally, whole blood can induce natural transformation, and other bodily fluids can induce organism-specific affects.17
This combination of factors suggests that antimicrobial susceptible A. baumannii may readily acquire resistance genes through MGE in vivo, with the likelihood of HGT increasing in the presence of specific bodily fluids. Preventing the transfer of AMR genes would aid in curtailing the further spread of MDR to current and future antimicrobial therapies. Unsurprisingly, this is not a new concept and strategies for limiting HGT have been discussed previously. The most promising approaches are targeting inhibiting recombination pathways in the recipient cell by manipulating CRISPR-Cas and restriction modification systems, or targeting the donor cell by attempting to induce defects in the conjugation mechanism by restricting the relaxasome.18
,19
While these strategies have been suggested, there is little progress on how exactly these strategies may be implemented. Regardless, given the importance of gene acquisition to the development and propagation of AMR in A. baumannii, a greater focus should be given to developing therapeutic approaches that can inhibit gene transfer, so that both current and future therapeutics may have more sustained utility.Stress responses
Further key factors for the success of A. baumannii as a healthcare acquired pathogen is its ability to resist both biotic and abiotic stresses. These pressures can encompass a range of different reactions, including responses to desiccation, disinfectant, oxidative stress, as well as adapting to the host environment, and regulating nutrient acquisition mechanisms that impact directly on virulence. A combination of these differing traits is likely to permit A. baumannii to persist in a spectrum of healthcare environments
20
; therefore, it is worth considering how these pathways may be disrupted to restrict survival in these environments.A wide range of mechanisms control stress response in A. baumannii and several master regulator proteins have been identified over the past decade. Specifically, two of these regulators (UspA and GigA/GigB) may be suitable targets for novel treatment approaches.
21
,22
Universal stress protein A (UspA), was recently characterised by Elhosseiny et al., who studied its role in physiology and virulence.- Gebhardt M.J.
- Shuman H.A.
GigA and GigB are master regulators of antibiotic resistance, stress responses, and virulence in Acinetobacter baumannii.
J Bacteriol. 2017; 199 (PMID: 28264991; PMCID: PMC5405210): e00066-17https://doi.org/10.1128/JB.00066-17
21
Here, the function of UspA was investigated by comparing wild type (WT) A. baumannii, with isogenic mutants, and organisms overexpressing UspA. The resulting data found that UspA is integral to H2O2 sensitivity, resistance to the 2,4-DNP respiratory toxin, sensitivity to low pH, and was associated with lethality in a murine model of sepsis.21
While the downstream mechanisms of UspA have yet to be elucidated, this work also described the relationship between UspA in A. baumannii and other Gram-negative bacteria; however, the closest homologue can be found in Staphylococcus aureus.21
The conserved nature of this protein, along with its range of functions in virulence and stress resistance, may make this protein a potential target for novel therapeutics. To date, little work has been performed exploring the potential of therapeutics targeting UspA. However, a study testing UspA as a carrier protein for lipooligosaccharide-based conjugate vaccines targeting the Gram-negative bacterium Moraxella catarrhalis, found that when tested in a murine model, high titres of anti-UspA antibody (IgG) were produced.23
The observation that UspA is highly immunogenic may make it a candidate for future antibody-based therapies and more traditional small molecule approaches.A further set of proteins that are key regulators of the stress response of A. baumannii's are GigA and GigB. These two proteins form a two component system which regulate a large number of responses against environmental stressors.
22
Unlike UspA, GigA/GigB have comparatively well characterised downstream targets, with one proposed model suggesting that GigA (activated by an unknown stimulus) dephosphorylates GigB, which in turn dephosphorylates the NPr, releasing σE for the transcription of genes involved in response to heat, low pH, and AMR.- Gebhardt M.J.
- Shuman H.A.
GigA and GigB are master regulators of antibiotic resistance, stress responses, and virulence in Acinetobacter baumannii.
J Bacteriol. 2017; 199 (PMID: 28264991; PMCID: PMC5405210): e00066-17https://doi.org/10.1128/JB.00066-17
22
While alternatives to this model exist, the central feature of GigA/GigB within these models makes them particular attractive targets for novel therapeutics. In ΔgigA and ΔgigB mutants, in vitro growth under different stress conditions are severely restricted- Gebhardt M.J.
- Shuman H.A.
GigA and GigB are master regulators of antibiotic resistance, stress responses, and virulence in Acinetobacter baumannii.
J Bacteriol. 2017; 199 (PMID: 28264991; PMCID: PMC5405210): e00066-17https://doi.org/10.1128/JB.00066-17
22
; therefore, the use of therapeutics to restrict the activity of GigA/GigB may impact on the ability of A. baumannii to resist stress and induce infection. It is important that further exploratory work is conducted on this system, as in vivo effects are not known and as it is also undetermined if this system in well conserved in other Gram-negative organisms or within Acinetobacter spp.- Gebhardt M.J.
- Shuman H.A.
GigA and GigB are master regulators of antibiotic resistance, stress responses, and virulence in Acinetobacter baumannii.
J Bacteriol. 2017; 199 (PMID: 28264991; PMCID: PMC5405210): e00066-17https://doi.org/10.1128/JB.00066-17
22
- Gebhardt M.J.
- Shuman H.A.
GigA and GigB are master regulators of antibiotic resistance, stress responses, and virulence in Acinetobacter baumannii.
J Bacteriol. 2017; 199 (PMID: 28264991; PMCID: PMC5405210): e00066-17https://doi.org/10.1128/JB.00066-17
In addition to master regulators, a host of different factors controlling specific stress responses have also been identified and may also be novel therapeutic targets. One of the reasons that A. baumannii can successfully persist in healthcare environments is its ability to resist desiccation, disrupting this process may prevent nosocomial infections in vulnerable patients. A major regulator of desiccation tolerance is the two-component system BfmR, which controls the expression of KatE, an important protein for survival during long-term drying.
24
This system also contributes to H2O2 susceptibility, nutrient stress, and increases in osmolarity, providing a link between persistence in the environment and pathogenicity.24
BfmR has already been studied as a potential target for new therapeutics, as the deactivation of BfmR appears to increase susceptibility to specific antimicrobial classes.25
This study also identified several sites within the protein structure, such as the dimerization interface and the phosphorylation site, that could be targeted. However, these targets would likely require a new class of antimicrobials which may also have utility in other bacterial spp. with suitable homologues.25
While the development of a novel class of drugs hold potential for treating A. baumannii infections, especially infections caused by MDR organisms, a drug targeting BfmR is likely to have the biggest effect by disrupting resistance to desiccation in a healthcare environment. However, the use of such a drug on a large scale would likely lead to development of resistance and alternative means of disrupting environmental resistance may be preferable for A. baumannii control.Aside from desiccation, another mechanism facilitating A. baumannii persistence in healthcare environments is reduced susceptibility to disinfectants, particularly chlorhexidine and ethanol. Chlorhexidine is commonly used in both healthcare and communal settings and acts as a bisbiguanide antimicrobial; A. baumannii is commonly resistant due to a family of chlorohexidine efflux pumps.
26
Efflux pumps are a common mechanism in which bacteria develop AMR and they attract considerable interest as targets for new drugs. A review considering the development of efflux pump inhibitors for the treatment of Gram-negative bacteria, suggested that peptidomimetics, arylpiperazines, and serum compounds had the greatest promise in combatting resistance in A. baumannii.27
The current focus of efflux pump inhibitors is geared towards combating AMR; however, a similar strategy could be adopted in combating resistance to chlorhexidine. A. baumannii is typically vulnerable to high concentrations of ethanol, whilst lower concentrations have actually been shown to influence virulence.28
,29
A. baumannii possess the ability to breakdown ethanol at low concentrations into several downstream products including Acetyl-CoA and Indole-3-acetic acid, which induces the stress response.28
,29
This response activates several regulators, including the previously described UspA, as well as stimulate the production of phospholipase C, which contributes to cytotoxicity.28
,29
Resistance to low concentrations of ethanol is worthy of further investigation, as the inappropriate or inconsistent use of ethanol as a disinfectant could be contributing to the development of increasingly virulent organisms in healthcare settings.A final major stress response that allows A. baumannii to persist both in the environment and during infection, is resistance to oxidative stress, particularly H2O2. The major transcriptional regulator of the response to H2O2 is OxyR, a canonical transcription regulator that inhibits bacterial growth in the presence of H2O2 while activating the expression of the H2O2 degrading enzymes KatE and AhpF1.
30
Restricting bacterial growth is particularly relevant, as reactive oxygen species (ROS) have shown to accumulate during the growth phase, while many DNA repair and protein repair process are activated during late stationary phase.31
OxyR is a particularly attractive target for new therapeutics, which is due in part to its overarching control of a major stress response. Additionally, new CRISPR-Cas9 tools for exploring the stress sensing mechanism of OxyR have already been constructed.32
The use of these tools may allow for streamlined development of therapeutics targeting OxyR, which would leave A. baumannii increasingly vulnerable to oxidative stress during infection and in the environment. The development of therapeutics targeting any one of these stress response mechanisms would greatly increase the sensitivity of A. baumannii to its environment, which may aid in clearing infections more quickly and possibly prevent infections from becoming established.Behaviour and biofilm formation
One of the major contributors to the success of A. baumannii is the ability to form biofilms. Biofilm formation may not be essential for the epidemic spread of A. baumannii, but they have been shown to play a key role in host-pathogen interactions, and are major contributors to medical device-associated infections and in AMR.
33
,34
Therefore, it is important to better understand how biofilms are formed and if we can identify potential targets for therapeutics designed to disrupt their formation.The ability to form biofilms is closely is associated with both genes that facilitate their formation biofilm and AMR.
35
There are four known genes that are closely associated with biofilm formation, there are: bap, which plays a role in intercellular adhesion and establishment of biofilms; blaPER-1, which primarily plays a role in regulating adhesion to epithelial cells; csuE, which facilitates pili formation; and ompA, which enhances biofilm formation on plastic surfaces.35
, 36
, 37
The formation of biofilms on biotic surfaces such as epithelial cells, while not necessarily correlated with worse outcome during infection, are strongly associated with AMR.
35
,38
It has been found that there is differential expression of genes controlling biofilm formation, including genes regulating pili, efflux pumps, and virulence factors when A. baumannii is exposed to sub-inhibitory concentrations of antimicrobials, specifically Meropenem and Tigecycline.39
This promotion of biofilm formation due to sub-inhibitory concentrations of antimicrobials leads to an increase in minimum inhibitory concentrations (MIC) and the minimum biofilm eradication concentration of these antimicrobials. This was thought to be due the exopolysaccharide matrix or the overexpression of efflux pumps.39
Overexpression of efflux pumps in particular seems to be a major feature of A. baumannii biofilms, this process is a major contributor to the development of AMR and may an approach for novel therapies.40
However, given the role of biofilm formation in AMR, an alternative strategy may be to attempt to prevent biofilm formation from occurring in vivo. One potential target may be the Bap protein, a large surface protein that is required for water channel formation and biofilm formation on abiotic surfaces and eukaryotic cells.41
Disrupting the ability to adhere to epithelial cells would greatly reduce AMR and aid the immune system in clearing an A. baumannii infection. Bap is currently the only surface protein associated with this property, and thus warrants further investigation as a therapeutic target.While the formation of biofilms of biotic surfaces represents a major challenge for AMR, their formation on abiotic surfaces are one of the main reasons why A. baumannii is able to persist in the environment as a primary cause of medical device associated infections. Binding to abiotic sites is achieved through the Csu pili, a form of archaic pili that possess finger-like loops, which are exposed by CsuE, that can bind to hydrophobic cavities in abiotic surfaces, differentiating them from classical pili.
37
Two possible strategies can be utilised to disrupt this binding. Firstly, the use of hydrophilic materials in the production of medical devices would provide a cost-effective manner to reduce A. baumannii infections. In regions where this process may not be possible, the development of a therapeutic targeting proteins that can regulate binding to abiotic surfaces may provide some utility in treating medical device-associated infections. The finger-like loops of the Csu pili would be a potential candidate, an anti-tip antibody has already been shown to completely block biofilm formation, though the potential of this mechanism has yet to be translated into a viable treatment option.37
OmpA has also been shown to play a role in the adhesion to abiotic surfaces, but this mechanism remains poorly described.42
However, OmpA may prove to be more attractive target, as it plays a variety of roles in other processes, including the development of AMR, and has already attracted attention as a therapeutic target.43
Interactions with the host
When assessing how to best treat A. baumannii infections, approaches that modify host-pathogen interactions may offer the best potential for success. These types of interactions are likely to vary depending on the site of a given infection (e.g. different cellular interactions during pneumonia and bacteraemia) and potential therapeutics may be developed that target universal host interactions or more specific cell types. This specific area appears hold a large amount of potential, especially as a large number of studies have been published in recent years through the development of in vivo models and advances in sequencing technology which examine the transcriptome and differential gene expression.
One of the best studied sites of host-pathogen interaction is the human airway. A proteomic analysis of A. baumannii in the human airway identified differential expression of 179 proteins, the most noteworthy being the upregulation of the OmpA and YjjK virulence factors.
44
Similar patterns were identified in response to exposure to mucin with 427 predicted protein-encoding genes showing differential expression, specifically genes associated with virulence and biosynthetic pathways, which allow of the use of mucin as a nutrient source.45
However, while it is generally known that exposure to the host environment alters the behaviour of A.baumannii, the mechanisms for how this process occur are not well understood. This limitation leaves major gaps in our current understanding and ability to highlight novel targets for A.baumannii infection but further study of these mechanisms may elucidate novel ways of both treating in vivo infections as well as reducing virulence. Fortunately, several models for studying the mechanisms underlying the response of A. baumannii to the host environment have been developed in recent years, specifically focusing on pneumonia in mice and rats.46
, 47
, 48
While these models are currently limited to studying specific aspects of A. baumannii pathology, future use could allow for the further studying of how A. baumannii responds to the host environment and thus provide a possible mechanism to actively limit virulence in vivo.Lastly, another important aspect of A. baumannii-host interaction is the impact on the immune response. This is a key area in identifying potential targets to limit induced immunopathology, particularly as there is a positive correlation between virulence of specific organisms and the extent of the pro-inflammatory immune response.
49
While many Pattern Recognition Receptors (PRRs) recognise bacterial infections, two of the most important in A. baumannii infections are TLR2 and TLR4.50
One of the major stimulators of these receptors during A. baumannii induced pneumonia is the release of outer membrane vesicles.51
The release of these outer membrane vesicles stimulates the release of several important pro-inflammatory cytokines including IL-1β, TNF-α, IL-6, INF-γ, which are mediated by TLR2 and TLR4. The release of these pro-inflammatory cytokines leads to the attraction of phagocytes and the activation of complement but can also lead directly to tissue damage. This injury to host tissue may be exaggerated by the fact that A. baumannii possess some resistance to the complement system, a key aspect of innate immunity. This resistance is facilitated by a combination of polysaccharide capsules and the active degradation of C3b using the plasminogen-binding protein, CipA.52
,53
A reduction of the pro-inflammatory cytokine response through the targeting or sequestering of outer membrane vesicles and other pro-inflammatory stimulants, such as LPS, may be an effective way of reducing immune-mediated damage during infection, though this must be balanced with the clearing of the infection by the immune system. To this end, improving the efficiency of the pro-inflammatory response by inhibiting proteins such as CipA, allowing the more efficient activation of complement, may make of a powerful combination therapy that would allow of improved clearance of the infection without causing excess tissue damage.Conclusions
While A.baumannii remains a major public health challenge it also remains comparatively poorly understood. The ability of A. baumannii to rapidly acquire resistance to antimicrobials means that we need new approaches for novel drug targets and strategies that can either negate traditional means of developing resistance or that prevent the initial transmission and establishment of A. baumannii infections. Here, we aimed to highlight some key aspects of A. baumannii virulence and resilience, in addition we have discussed some of novel therapeutic approaches that warrant further investigation as a next generation of antimicrobial treatments for A. baumannii.
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Declaration of Competing Interest
The authors declare no competing interests.
Funding
This work was supported by a Welcome senior research fellowship to SB to (215515/Z/19/Z) and the Medical Research Council [grant number MR N013433-1]. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Acknowledgments
We wish to acknowledge all members of the Translational microbiology and international health group at the University of Cambridge for their input on the scope of this review.
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Published online: October 25, 2020
Accepted:
October 21,
2020
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