Alternatives to Antibiotics

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1		Xinhai Chen	--	2459	2023-01-11 10:33:07	\|
2	format	Jason Zhu	Meta information modification	2459	2023-01-12 03:01:57	\|

This entry is adapted from the peer-reviewed paper 10.3390/antibiotics12010067

Infections caused by antibiotic-resistant bacteria (ARB) are one of the major global health challenges. In addition to developing new antibiotics to combat ARB, sensitizing ARB, or pursuing alternatives to existing antibiotics are promising options to counter antibiotic resistance. Anti-ARB strategies include the following: (i) discovery of novel antibiotics by modification of existing antibiotics, screening of small-molecule libraries, or exploration of peculiar places; (ii) improvement in the efficacy of existing antibiotics through metabolic stimulation or by loading a novel, more efficient delivery systems; (iii) development of alternatives to conventional antibiotics such as bacteriophages and their encoded endolysins, anti-biofilm drugs, probiotics, nanomaterials, vaccines, and antibody therapies.

antibiotic resistance new antibiotics bacteriophages vaccine

1. Introduction

Scientists always suggest that the use of antibiotics should be prudent. However, the definition of the term “prudent use” is nebulous. Determining which antibiotics are appropriate or what precise dosage needs to be given to patients remains a challenge for clinicians, even according to the standard medication guidelines. Nonetheless, the key to being prudent about using antibiotics is the use and development of effective alternatives to antibiotics. Successful application of antibiotic alternatives can decrease antibiotic use and hinder the emergence of antibiotic-resistant bacteria (ARB).

2. Bacteriophages and Their Encoded Endolysins

In terms of treating bacterial infections, bacteriophage (phage) therapies preceded antibiotic treatment ^[1]. Phages are duplodnaviria viruses that can exclusively lyse bacteria without harming host cells. Since the introduction of broad-spectrum antibiotics in the 1940s, the development of phage therapy has halted. However, with the emergence of ARB, phage therapy is regaining attention. Currently, several products based on phage therapy are commercially available in some Eastern European countries, while a number of clinical or preclinical studies on phage therapy have been conducted in different countries worldwide. One randomized phase 1/2 trial in France and Belgium evaluated the efficacy and tolerability of a cocktail of phages in patients with P. aeruginosa wound infection ^[2]. Unfortunately, due to the highly unexpected low concentration of phages after manufacturing, this phage therapy showed a slower efficiency in decreasing bacterial load than the standard treatment of burn wounds and needs to be further fine-tuned by increasing phage concentration and evaluated in a large sample of participants ^[2]. Nonetheless, several case reports originating from China and the United States have shown that phage administration with or without antibiotic treatments could protect patients against multidrug-resistant A. baumannii infection ^[3]^[4]^[5], demonstrating the potential of phage therapy against ADR infections in appropriate doses. However, phage bacterial resistance and their immunogenicity are two additional unresolved drawbacks of phage therapy.

Phages employ multiple steps to perform their lytic cycle, primarily by utilizing endolysins, the enzymes that lyse the bacteria by degrading peptidoglycan ^[6]. Endolysins can be designed to have specificity towards different species of GNBPs and GPBPs. A study reported four recombinant endolysins that could effectively lyse one hundred GNBPs, including multidrug-resistant K. pneumoniae, Salmonella, P. aeruginosa, E. coli, A. baumannii, and Enterobacter spp. strains ^[7]. An endolysin (Ply6A3) directly purified from phages showed high antibacterial activity against A. baumannii, E. coli, and MRSA ^[8]. A new anti-MRSA endolysin, rSAL-1, has been developed and tested as a drug (SAL200), which showed no serious adverse effects in phase-1 of clinical trials ^[9]. SAL200 is the first endolysin-based drug to be approved for treating human skin infections caused by S. aureus, including MRSA ^[10]. This therapy was highly effective on both chronic and recurrent S. aureus-related dermatoses without selecting for bacterial resistance after long-term daily treatment. Another endolysin-based drug, Exebacase, has been developed to treat staphylococcal bloodstream infections, by ContraFect Corporation and is currently in phase 3 of clinical studies ^[11]. During phase 2, with the aid of standard care antibiotics, a single intravenous infusion of this drug could help patients to combat S. aureus bacteriemia and endocarditis ^[12].

3. Anti-Biofilm Drugs

Biofilms are a well-known problem in the treatment of bacterial infections. They profoundly hinder the penetration of antibiotics and favor the development of resistance. Thus, biofilm-related infections are impossible to treat with conventional antibiotics. The attachment of bacteria to a surface is the first step in the formation of biofilms. Targeting the initial attachment can be a reasonable strategy to prevent biofilm formation. Mannosides are small molecules that target FimH, an adhesion protein of type 1 pili in E. coli ^[13]. The administration of monomeric biphenyl mannosides prevented the formation of uropathogenic E. coli biofilm in vitro and blocked the adherence and invasion of this bacteria in animal models ^[14]. Antigen 43 and curli fibers are two additional types of adhesion molecules mediating the attachment of bacteria on biotic and abiotic surfaces ^[15]. Two curlicides (FN075 and BibC6) derived from ring-fused 2-pyridones have been developed to inhibit the biosynthesis of curli fibers needed for biofilm formation ^[16]. Peptides with anti-biofilm activity (anti-biofilm peptides) are new solutions for biofilm inhibition. Anti-biofilm peptides IDR-1018, DJK-5, and DJK-6 inhibited biofilm formation in multiple GNBPs and GPBPs by binding and degrading guanosine tetraphosphate (ppGpp), which is one of the second messenger nucleotides that sense nutrient starvations and contribute to the antibiotic resistance and biofilm formation ^[17]^[18]. In addition, the phage-encoded depolymerases have anti-biofilm activity, as demonstrated by their ability to degrade extracellular polymers and related biofilm components ^[19]. A depolymerase from φAB6 phage digested capsular polysaccharide, inhibited the colonization of A. baumannii on the surface of medical devices, and suppressed A. baumannii infection in a zebrafish model ^[20]. Given the specific recognition of bacterial surface components by aptamers, utilizing aptamers as anti-biofilm agents is possible through the specific binding to certain constituents of the bacterial surface. For instance, three DNA aptamers were identified to bind with the flagellum, a crucial motile component that mediates tropism and initial attachment in the process of biofilm formation, with aptamer 3, having the best anti-biofilm activity ^[21]. Moreover, using aptamers that bind to the common constituents of both bacterial surface and biofilm is another anti-biofilm strategy. The six DNA aptamers that interacted with S. aureus biofilm were demonstrated to assist in the eradication of S. aureus biofilm when combined with liposomal delivery of vancomycin and rifampicin ^[22].

4. Probiotics

Probiotic supplementation is accepted globally as a beneficial health strategy despite the lack of scientific evidence of its alleged effects. Current mechanisms that explain the protective effect of probiotics are limited to the regulation of the immune system, enhancement of the intestinal epithelial barrier, competition with pathogenic bacteria for nutrients, and bacteriocin-mediated interference ^[23]. The contribution of the microbiome to host defense against pathogen colonization and prevalence is called “colonization resistance” ^[24]. Bacillus subtilis, a common strain of human gut microbiota and component of probiotic formulae, can produce bacitracin that interferes with the cell wall synthesis of MRSA and other GPBPs. However, in a randomized prospective study involving a 5-day treatment in healthcare workers, bacitracin was inferior to mupirocin for suppressing nasal S. aureus ^[25]. Besides bacitracin, B. subtilis produces fengycins, which are a family of lipopeptides. Fengycins exhibited a strong ability to block the S. aureus quorum-sensing system Agr, which is vital for S. aureus gut colonization ^[26]. These studies suggest a strong potential for using alive Bacillus strains as a probiotic therapy to prevent infections caused by S. aureus colonization. Besides natural probiotics, engineered or synthetic probiotics are an additional promising option. For example, an engineered probiotic E. coli Nissle 1917 equipped with quorum sensing and lysing devices sensed and killed 99% planktonic P. aeruginosa, and caused a 90% reduction in biofilm formation in an in vitro system ^[27].

5. Antibacterial Nanomaterials

Many nanomaterials have an inherent bactericidal activity through several well-accepted mechanisms, including oxidative stress response, physical disruption, altering bacterial metabolism, protein denaturation, and disrupting DNA replication ^[28]. Normally, the bacterial cell envelope is negatively charged, and electrostatic interaction can be achieved by designing positively charged nanoparticles. Gold nanoparticles caused bacterial membrane tension and squeezing, resulting in physical damage to the cell envelope and subsequent cell lysis ^[29]. Other metal nanoparticles, such as silver and copper, could also destroy the bacterial cell wall/membrane ^[30]^[31]. Silver nanoparticles are capable of damaging peptidoglycan structure by generating reactive oxygen species ^[32]. Copper nanoparticles reduced the expression of a bacterial glucose transporter and the activity of nitrate and nitrite reductases ^[33]. With selected bacteria as the target, the cationic polymer coating of nanoparticles showed antibacterial activity by destroying bacterial cell plasma membrane, inhibiting bacterial proliferation, and preventing biofilm formation through strong electrostatic interaction with the negatively charged bacterial membrane ^[34]. These single-element nanoparticles show nontargeted antibacterial activity, while the development of composite nanoparticles may increase specificity and reduce the damage to microbiota. Based on the differences in the cell envelope structure between gram-positive and gram-negative bacteria, gold nanocomposite particles based on amino sugars with a narrow spectrum antibacterial activity and a gram-positive antibacterial action were developed ^[35]. Graphene oxide-silver (GO-Ag) nanoparticles had differential inhibitory effects on gram-negative E. coli and gram-positive S. aureus ^[36]. GO-Ag nanoparticles showed a bacteriostatic effect towards E. coli and S. aureus by destroying the integrity of bacterial cell walls, and inhibiting the cell division cycle, respectively.

6. Vaccines

Vaccines are always the first choice to prevent infectious diseases. Compared to the relatively simpler viruses, fewer vaccines are clinically available for bacteria. As of 2019, FDA approved 65 and 32 vaccines to prevent diseases caused by viruses and bacteria, respectively. These bacteria were B. anthracis, M. tuberculosis, Vibrio cholerae, Clostridium tetani, H. influenzae, Neisseria meningitidis, Yersinia pestis, S. pneumoniae, and Salmonella typhi, which do not include the nosocomial ESKAPE pathogens. No vaccine against ESKAPE pathogens is available, though not for lack of trying as demonstrated by dozens of clinical trials that have failed so far. In earlier clinical trials, vaccinating whole cells or cell lysates of pathogens such as K. pneumoniae and S. aureus exhibited a limited protection with relatively high toxicity ^[37]^[38]. StaphVAX, a vaccine that targeted S. aureus capsular polysaccharide types 5 and 8 (CP5 and CP8), was assessed in two phase III studies and eventually displayed no benefit for the recipients with bacteremia ^[39]. The IsdB vaccine V710 also failed in a phase III randomized controlled trial of S. aureus infection ^[40]. Pfizer’s SA4Ag vaccine, targeted multicomponent antigens MntC, ClfA, and both CP5 and CP8, was still insufficient in providing protective immunity against S. aureus in the bloodstream and surgical site infections in patients who had undergone spinal surgery ^[41]. Two LPS-targeted vaccines were unsuccessful in reducing the rate of P. aeruginosa colonization and the frequency of P. aeruginosa infection in patients with cystic fibrosis ^[42]^[43]. The vaccine IC43 consisting of two P. aeruginosa OMPs, OprF, and OprI, had no significant effect on invasive P. aeruginosa mortality and infections in a phase III study ^[44]. These clinical studies urge scientists to dissect disappointing results in the hope of finding ways to overcome failures. Recent studies strongly suggest that prior exposures to bacteria by colonization seem to cause the ineffectiveness of vaccines in humans. Such bacteria that are commonly found in human microbiota include E. faecium, S. aureus, K. pneumoniae, and some Enterobacter strains ^[45]^[46]. The pre-existing human-S. aureus interaction jeopardizes immune responses to many staphylococcal antigens ^[47]^[48]^[49]^[50]. Thus, in humans who have been previously exposed to S. aureus, new vaccination with those antigens is incapable of conferring protective immunity. Overcoming this obstacle of prior S. aureus exposures can be achieved at least by immunizing the antigen epitopes that only develop protective immunity or that have no immune response during S. aureus exposures. Staphylococcal protein A (SpA) is one such antigen that has no specific antibodies in humans and vertebrates after colonization or infection ^[51]^[52]. Two improved nontoxigenic SpA variants were developed and showed strong potential to reduce the rate of S. aureus bloodstream infection and nasal colonization ^[53], and now are being further studied.

7. Antibody Therapies

Antibodies can be used to prevent and treat diseases. In contrast to several of the aforementioned available clinical vaccines, only three FDA-approved antibody therapies for bacterial infections exist, two of which treat B. anthracis infection and the other one treats Clostridium difficile infection ^[54]. All of these antibodies consist of human immunoglobulin G (IgG) and recognize secretory toxins. However, many other antibody therapies targeting components of secretory toxins or cell envelopes of GNBPs and GPBPs have failed in clinical trials ^[54]. Protective antigen epitopes are important, and most antigens contain both protective and nonprotective epitopes. Thus, the antibodies uniquely recognizing protective epitopes are more likely to have a therapeutic effect on infections. For instance, in previously S. aureus-exposed hosts, antibodies elicited from NEAT2 but not the NEAT1 domain of IsdB provided protection against secondary S. aureus infection ^[50]. More importantly, out of three monoclonal antibodies (mAbs) recognizing the NEAT2 domain, only one (mAb 1C1) provided protection under the above infection circumstances because it resisted competition by antibodies induced by previous S. aureus exposures. Other factors besides the appropriate paratope, including isotype, antibody titer, half-life, antigen-binding affinity, N-297 glycosylation, downstream effectors (complement C1q, FcγRs), and bacterial evasion strategies, can also impact antibody functions against bacterial infections. A mAb 3F6 recognizing the IgG-binding protein (IBP) nSpA, exerted anti-S. aureus activity only under high N-297 galactosylation or afucosylation conditions ^[55]. The favorable glycosylation enhances the antibody 3F6-IgG interaction with C1q or FcγR, strengthening their opsonophagocytic killing (OPK) of S. aureus. Distinct evasion strategies specific to antibodies have been explored in different bacteria. For instance, S. aureus can inhibit antibody functions by producing SpA and IgG-degrading V8 proteases ^[56]^[57]. SpA captured the Fc region of IgG, keeping it from binding to FcγRs, C1q, and FcRn and resulting in decreased OPK activity and half-life of IgG ^[58]. Notably, mAb IgG variants with R-QVV and R-DDRVV substitutions in the Fc region could disrupt SpA interference improving therapeutic activity in humanized FcRn mouse models. Furthermore, S. pyogenes and P. aeruginosa secreted IgG-degrading enzymes, which cleaved the hinge region or N-glycosylation of IgG ^[59]^[60]. In samples collected from patients with S. pyogenes, IgG-Fc was found to bind on the surface IBPs of S. pyogenes, along with the detection of cleavage of N-glycosylation of IgG ^[60]^[61]. In conclusion, future directions of generating antibody therapies against bacterial infections should simultaneously consider their paratopes that bind with protective epitopes and their modification by engineering to overcome IgG-specific evasion strategies.

Other antibody engineering options for combating bacterial infections have been reported. DSTA4637S is an antibody-antibiotic conjugate that combines a rifampicin-class antibiotic with an engineered human IgG1 that specifically binds to N-acetyl-glucosamine of WTA ^[62]. This conjugate is designed to kill intracellular reservoirs of S. aureus. When DSTA4637S-opsonized S. aureus is taken up by host cells, phagolysosomal proteases cleave the linker between antibody and antibiotic releasing the antibiotic in sufficient concentrations to kill the bacteria. MEDI13902 is a bispecific antibody against P. aeruginosa PcrV, a protein located at the top of the type III secretory system, and Psl, an extracellular polysaccharide ^[63]. This antibody therapy is currently in phase II of the clinical trial to evaluate the effectiveness and safety issues in mechanically ventilated patients. Antibody engineering has been widely used in cancer immunotherapy ^[64] but has only just begun for bacterial infections. Further investigations considering multiple host and bacterial factors are expected to result in promising antibody therapies.

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Subjects: Infectious Diseases

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Jinzhou Ye

Xinhai Chen

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Update Date: 12 Jan 2023

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