Novel Therapeutic Strategies against Multi-Drug Resistant Pseudomonas aeruginosa: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Changhong Yin.

Pseudomonas aeruginosa (P. aeruginosa) with multi-drug resistance (MDR) is a major cause of serious healthcare-associated infections, leading to high morbidity and mortality. This opportunistic pathogen is responsible for various infectious diseases, such as those seen in cystic fibrosis, ventilator-associated pneumonia, urinary tract infection, otitis externa, and burn and wound injuries. Due to its relatively large genome, P. aeruginosa has great diversity and can use various molecular mechanisms for antimicrobial resistance. 

  • Pseudomonas aeruginosa
  • lipopolysaccharide
  • porin
  • multi-drug resistance
  • phage therapy

1. Introduction

Pseudomonas aeruginosa (P. aeruginosa) is a common opportunistic human pathogen. It often causes various complicated acute and chronic infections in immunocompromised hosts. P. aeruginosa can multiply and become the main pathogen in cystic fibrosis (CF) patients, ventilator-associated pneumonia, urinary tract infection, otitis externa, burn and wound injuries, bone and joint infections, and systemic infections. Antimicrobial resistance (AMR) is an urgent global public health threat resulting in the death of at least 1.27 million people worldwide and was associated with nearly 5 million deaths in 2019 [1].
The molecular mechanisms of AMR are complex. The continuous use of various antibiotics over the years has led bacteria to accumulate various AMR mechanisms [8,9][2][3]. AMR in P. aeruginosa can be caused by low outer membrane (OM) permeability, drug-resistant efflux pumps, the presence of antibiotic resistance genes, the formation of biofilms, etc. Noticeably, multiple mechanisms are simultaneously present, resulting in resistance to nearly all antibiotics available against P. aeruginosa [10][4]. AMR mostly depends on the structure and composition of the bacterial cell surface, especially alterations in the OM of Gram-negative bacteria. The OM acts as a frontline defense against hostile environments. The extensively drug-resistant (XDR) P. aeruginosa is highly related to low OM permeability. The characterization of the OM is essential for understanding how antibiotics penetrate this barrier, and for the subsequent development of new therapeutic strategies. 

2. Mechanisms of Antimicrobial Resistance Targeting LPS and Porins

P. aeruginosa has an asymmetric OM composed of phospholipid in the inner leaflet and lipopolysaccharide (LPS) glycolipid in the outer leaflet, compared to a cytoplasmic inner membrane (IM) with a symmetric phospholipid bilayer. LPS has received much attention because of its ability to stimulate the host immune system as an endotoxin [11][5]. It is now known that OM provides a highly selective permeability barrier against many toxic compounds such as host antimicrobial peptides and antibiotics, as well as both lipophilic and hydrophilic compounds, including nutrients. The high selectivity of the OM in P. aeruginosa is mainly attributed to the presence of LPS [12][6].

2.1. LPS Biosynthesis

LPS is a major surface molecule of Gram-negative bacteria and consists of three distinct domains: lipid A, the hydrophobic portion of LPS that anchors the molecule in the OM; core oligosaccharide; and O antigen, an extended polysaccharide chain extending into the extracellular environment. Lipid A is essential for bacteria growth. Mutants with reduced lipid A biosynthesis grow slowly and are sensitive to a wide range of antibiotics [13][7]. The absence of lipid A impedes the aggregation of LPS, leading to bacteria cell death [14][8]. The biosynthesis of lipid A relies on a zinc-dependent metalloamidase, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). Owing to the critical role of LpxC in lipid A biosynthesis and its lack of homology with mammalian proteins, LpxC inhibitors are expected to be potential antibiotics for the treatment of Gram-negative bacterial infections [15,16,17][9][10][11]. An extensive research effort has focused on the discovery of novel LpxC inhibitors against P. aeruginosa. CHIR-090 was the first reported LpxC inhibitor in 2005 [18][12]. Another two compounds, ACHN-975 [19,20][13][14] and PF-5081090 [21][15], discovered later, exhibit extensive antimicrobial activity. These two LpxC inhibitors are more active against P. aeruginosa with lower minimal inhibitory concentration MIC90 (0.5~1 μg/mL) and IC50 (1.1 nM) than CHIR-090 [22,23][16][17]. However, few inhibitors of LpxC have reached clinical trials, largely due to the limited efficacy and unfavorable cardiovascular toxicity of the candidate inhibitors tested [24][18]. LPS biosynthesis requires both UDP-N-acetylglucosamine (UDP-GlcNAc) and acyl-ACP molecules. Both are also necessary for the biosynthesis of peptidoglycan (PG) and phospholipid, respectively, though LPS and PG have individual synthesis pathways [26][19]. The coordination between these essential surface layers of the OM has not been made clear. It was not until recently that the discovery of a regulatory interaction between the dedicated enzyme involved in the PG and LPS synthesis pathways in P. aeruginosa was made.

2.2. LPS Modification

P. aeruginosa has intrinsic, acquired, and adaptive resistance to a variety of antimicrobials. Antimicrobials are becoming increasingly ineffective, as MDR spreads quickly, leading to infections that are difficult and sometimes impossible to treat. Polymyxins have been revived as the last-line defense against infections by MDR Gram-negative bacteria. Colistin (polymyxin E) targets LPS through the modification of lipid A, which competitively interacts with the anionic lipid A, displacing divalent Ca2+ and Mg2+ ions to destabilize the OM, subsequently disrupting the IM, leading to cell death [29][20]. Colistin resistance in Gram-negative bacteria can be chromosomal or plasmidmediated. The first case of plasmid-mediated colistin resistance conferred by the mcr-1 gene in Enterobacteriaceae was reported in 2016. It was observed that P. aeruginosa transformed with mcr-1 demonstrated elevated colistin MIC from 0.5 mg/L to 8 mg/L and polymyxin B MIC from 0.5 mg/L to 4 mg/L [30][21], suggesting the potential emergence and spread of plasmid-borne colistin resistance threating human health. Most common mechanisms conferring resistance to colistin are directed against modifications of the lipid A moiety of LPS with the addition of positively charged moieties, such as phosphoethanolamine (pEtN) and 4-amino-4-deoxy-L-arabinose (L-Ara4N), resulting in a reduction in colistin affinity [31,32][22][23].

2.3. LPS Transport

LPS synthesis and transport pathways are attractive targets for the development of new antimicrobial therapeutics. LPS transport requires MsbA and Lpt proteins. MsbA is a member of the ABC transporter superfamily and performs the first step of LPS transport by flipping core LPS across the IM [38][24]. LPS is then transported to the cell surface via the Lpt pathway [39][25]. Two inhibitors targeting MsbA are reported. Inhibitor G907, a quinolone-like compound, binds to the transmembrane pocket of MsbA and locks the protein in an inward-facing LPS-bound conformation [40][26]. However, this inhibitor is less effective in P. aeruginosa. Another MsbA inhibitor, tetrahydrobenzothiopene, stimulates the ATPase activity of MsbA and causes the decoupling of ATP hydrolysis from LPS [41][27]. Recently, a study on tetrahydrobenzothiopene derivatives was reported. The in vitro evaluation showed that most of the target compounds exhibited a great potency in inhibiting the growth of bacteria. One candidate showed MIC values of 1.1 μM against E. coli, 1.0 μM against P. aeruginosa, 0.5 μM against Salmonella, and 1.1 μM against S. aureus. This demonstrates a promising lead compound for the development of new antimicrobial agents against MDR and persistent bacteria [42,43][28][29]. Recently, the biological effects of verapamil, an inhibitor of ABC transporters, were investigated in P. aeruginosa. It was noticed that IC50 for novobiocin decreased 34% in the presence of verapamil [44][30]. Verapamil did not inhibit P. aeruginosa growth but increased its sensitivity to novobiocin. The molecular modulization of protein MsbA followed by a docking analysis revealed that novobiocin and verapamil interacted at a common site on MsbA protein. The result indicates that both novobiocin and verapamil act as MsbA potential competitive inhibitors. Lpt proteins represent another promising target for developing new classes of antibiotics. Murepavadin (POL0780) is a peptidomimetic antibiotic that interacts with the LPS transporter LptD to block LPS assembly and insertion into the OM [45][31]. As the first OM protein-targeting antibiotic to enter late-stage clinical development, murepavadin displays both potent activities in vitro against P. aeruginosa, including MDR clinical isolates with MIC90 at 0.12 mg/L, and in vivo pharmacokinetics assays in mouse models of infection. It is known that colistin kills P. aeruginosa through the modification of lipid A on the OM. However, how it disrupts the inner membrane is not clear. Sabnis et al. [47][32] designed a new therapeutic approach and exposed P. aeruginosa to colistin and/or murepavadin. An MIC assay showed that murepavadin sensitized P. aeruginosa to colistin by increasing LPS abundance in the IM. In addition, in both in vitro clinical MDR isolates and an in vivo mouse model of lung infection, the combination therapy of colistin and murepavadin demonstrated enhanced efficacy in the killing and clearance of P. aeruginosa. These results also demonstrated that colistin exerts bactericidal activity by targeting LPS in the IM. 

2.4. Porins

The molecular characterization of the OM is essential for understanding how antibiotics penetrate this barrier, both for the development of new therapeutic strategies and for rational drug design. Porins are beta barrel pore proteins contained in the OM of Gram-negative bacteria. These proteins possess an internal hydrophilic channel that generally restricts the entry of most lipophilic molecules and only permits the passage of certain small hydrophilic molecules from the external environment to the interior cell [49,50][33][34]. OprF is the most abundant non-lipoprotein on the OM of P. aeruginosa. Owing to its C-terminal containing a PG-binding domain, OprF is mainly involved in maintaining the OM structure [58][35]. Mutations on OprF confirmed that its N-terminal is responsible for protein production and membrane insertion, while its C-terminal is liable for stable interaction with PG anchoring on the OM [59][36]. As OprF and OprI are highly conserved and induce a cross protective immunity across all P. aeruginosa strains, they become promising vaccine candidates for the control of P. aeruginosa infection. A phase III clinical trial of IC43, a hybrid OprF/I vaccine, has been completed [60][37]. OprF involves adhesion, biofilm formation, and virulence. In comparison to the wild-type, isogenic OprF mutant, and an OprF-complement strain, OprF is required for P. aeruginosa virulence as the OprF mutant strain displays reduced cytotoxicity in cells [61][38].  The high stability of P. aeruginosa OM is due to the presence of the OprH, the smallest porin found in P. aeruginosa. Edrington et al. [64][39] provided the first molecular structure of OprH and evidence for multiple interactions between OprH and LPS that likely contributed to the antibiotic resistance of P. aeruginosa. Carbapenem is a mainstay therapy for P. aeruginosa infection. In general, carbapenems can efficiently cross the OM by passing through the aqueous channels, such as OprD in P. aeruginosa. Reduced permeability caused by downregulated OprD protein appears to be the most common mechanism of intrinsic resistance to carbapenem [67][40]. Mutations in OprD [68,69,70,71,72][41][42][43][44][45] are associated with imipenem resistance and reduced susceptibility to meropenem through the loss of or change in OprD.

3. New Strategy Development against P. aeruginosa Infection

3.1. Phages

Bacteriophage therapy is one of the promising alternatives against MDR P. aeruginosa. Many research studies have demonstrated the ability of phages to eradicate P. aeruginosa [78,79,80][46][47][48]. Several clinical studies have been conducted to evaluate the effectiveness of phage therapy in treating specific P. aeruginosa infections (https://clinicaltrials.gov) (accessed on 20 December 2023). Phage therapy has so far failed to translate into positive outcomes in the limited number of clinical trials that have been performed. One problem is the rapid evolution of phage resistance, which limits the clinical efficacy of phage therapy. Yang et al. [82][49] strategically formulated a cocktail of phages that successfully suppressed the evolution of resistance. After prolonged incubation, phage resistance in P. aeruginosa was observed. Lipid remodeling during phage infection may alter binding and subsequent infection dynamics [83][50]. One case study described phage therapy for a complex bone and joint infection of XDR P. aeruginosa, in which phage therapy combined with ceftolozane/tazobactam and colistin resulted in rapid wound healing over 2 weeks [84][51].

3.2. Vaccines

Extensive research has focused on vaccine development against P. aeruginosa over the last 50 years. Four vaccines have entered phase III trials during these years. While some showed promising results, no anti-P. aeruginosa vaccine has yet been approved. LPS and OM proteins are important antigens of P. aeruginosa, which have been shown to be immunogenic for hosts. However, due to the high diversity of P. aeruginosa serotypes, it is hard to design a vaccine effective for all serotypes [87][52]. Octavalent O-polysaccharide-exotoxin A conjugate (Aerugen®) is an LPS-based conjugate vaccine. A phase I study showed high affinity IgG response to exotoxin and LPS in healthy volunteers. A phase II study initially showed similar immunoglobulin functions in CF patients not colonized with P. aeruginosa. Unfortunately, it did not have an impact on clinical outcomes. The phase III trial in CF patients was finally stopped as the interim results did not show significant differences between the placebo and control groups [88][53].

3.3. Nanoparticles

Photothermally active nanomaterials are emerging as potent antimicrobial agents [98][54]. Recently, a selective photothermal therapy based on LPS aptamer functionalized nanorods for MDR P. aeruginosa infection was reported [99][55]. Animal experiments showed that the nanorods permitted the active targeting of LPS on the surface of Gram-negative bacteria and a specific anti-inflammatory ability in the MDR P. aeruginosa-infected wound murine model. The combination of bacteria-imprinting technology and photothermal therapy has emerged as a potential therapeutic strategy for fighting drug-resistant bacteria [100,101,102,103][56][57][58][59]. A group of scientists reported a promising material: photothermal molecularly imprinted polymers (PMIPs) [104][60]. Based on the affinity of P. aeruginosa LPS with boric acid, LPS-imprinted PMIPs were synthesized for the study of the efficient capture and elimination of P. aeruginosa. Fluorescent images demonstrated that the engineered PMIP had low toxicity to normal cells, higher affinity to LPS, and more significant targeting capability toward P. aeruginosa than nonimprinted polymers. Although PMIP alone showed low anti-biofilm activity against P. aeruginosa in established biofilms, most viable cells were effectively eliminated by the combination of PMIP and irradiation near-infrared light therapy.

4. Challenges

The rapid growth of AMR/MDR is driven by the misuse and overuse of antibiotics that are commonly and widely used to treat bacterial infections. Antibiotics can wipe out harmful pathogens of concern and save lives. Simultaneously, antibiotics eradicate beneficial microbes, reduce microbiota diversity, and alter metabolic activity with deleterious consequences for human health [105][61]. Additionally, antibiotics may select bacteria with AMR to overgrow as these bacteria evolve and respond to the selective pressures placed upon them, whereas the combinatorial use of antibiotics can lead to the production and spread of MDR bacteria. P. aeruginosa is among the largest of the bacterial genomes with its genome size at a range of 5.5–7.0 million base pairs. This large genome facilitates P. aeruginosa’s evolutionary adaptation to diverse environments and development of resistance to antibiotics, phages, and/or vaccines. Additionally, P. aeruginosa possesses an abundance and diversity of bacteriophages, both lysogenic and lytic, driving bacterial evolution and providing a great source of phage candidates for phage therapy. However, few of these natural phages have been characterized in detail regarding their target specificity and toxic contents, leading to concerns about the safety, reliability, and efficacy of their applications. Recently, an increasing number of MDR P. aeruginosa clinical isolates have been whole-genome sequenced, revealing its high genome diversity, dynamic evolution, and MDR complexity. This diversity and complexity makes the prevention and treatment of MDR P. aeruginosa much more challenging. Notably, PAO1 and PA14 are the most commonly employed reference strains with moderate and hyper-virulent phenotypes, respectively. However, sequencing has demonstrated significant deviations from the clinical isolates of P. aeruginosa infection [107][62]. 

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