The emergence of antimicrobial resistance of Gram-negative pathogens has become a worldwide crisis. The status quo for combating resistance is to employ synergistic combinations of antibiotics. Faced with this fast-approaching post-antibiotic era, it is critical that we devise strategies to prolong and maximize the clinical efficacy of existing antibiotics. Unfortunately, reports of extremely drug-resistant (XDR) Gram-negative pathogens have become more common. Combining antibiotics such as polymyxin B or the broad-spectrum tetracycline and minocycline with various FDA-approved non-antibiotic drugs have emerged as a novel combination strategy against otherwise untreatable XDR pathogens. This review surveys the available literature on the potential benefits of employing antibiotic–non-antibiotic drug combination therapy. The apex of this review highlights the clinical utility of this novel therapeutic strategy for combating infections caused by ‘superbugs’.

According to the World Health Organization (WHO), antimicrobial resistance is one of the three greatest threats to human health [1]. The retreat of the pharmaceutical sector from new antibiotic discovery and development in favour of more profitable ‘lifestyle’ drugs, has led to the emergence of bacteria that are resistant to almost all clinically available antibiotics [15]. Confronted with the rapidly approaching post-antibiotic era, there is a critical need for medical innovation and we must develop strategies to prolong and maximize the clinical efficacy of existing antibiotics [6].

Repurposing of FDA-approved drugs for alternative indications is a highly effective strategy as these compounds have well-described toxicology, pharmacology and are already proven to be safe for human use that bypasses the costly and lengthy drug development pipeline [712]. Antibiotic–non-antibiotic combination therapies have been successfully used to treat infections caused by problematic pathogens such as Gram-negative and Gram-positive bacteria, tuberculosis, malaria and HIV for decades. Unfortunately, this traditional combination strategy is losing its lustre due to poor antimicrobial stewardship and widespread antibiotic resistance. The use of synergistic antibiotic–non-antibiotic combinations is emerging as a valuable tool for prolonging and maximizing clinical efficacy of existing antibiotics against problematic extremely drug-resistant (XDR) Gram-negative pathogens, i.e. Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. This review covers the contemporary literature and highlights the potential benefit of combining ‘old’ antibiotics with FDA-approved non-antibiotic drugs. The implementation of FDA-approved drugs for antibacterial combination therapy not only provides clinicians with new ‘off-the-shelf’ therapeutic options but also helps to expand the spectrum of current antibiotics against XDR strains. The fact that this is still an emerging field means there is a limited amount of literature on the topic, however, two ‘old’ antibiotics namely, polymyxin B and minocycline, have spear-headed to the forefront of this area and as such are the key focus of this review.

Minocycline–non-antibiotic combinations

Ejim et al. [5] investigated the synergistic antimicrobial effect of minocycline, a semi-synthetic tetracycline antibiotic in combination with 1057 FDA-approved drugs against one clinical isolate of P. aeruginosa, Escherichia coli and Staphylococcus aureus. Their screening efforts yielded 35 non-antibiotics that showed synergy with minocycline against S. aureus, 41 against E. coli and six against P. aeruginosa. For example, ascorbic acid, benserazide, chloroxine, tegaserod, loperamide and mitomycin displayed synergistic activity with minocycline against P. aeruginosa (Table 1). Benserazide, disulfiram, mitomycin and tegaserod showed synergistic antimicrobial activity against S. aureus. Notably, benserazide and loperamide in combination with minocycline showed synergistic activity against multidrug-resistant (MDR) minocycline resistant strains of P. aeruginosa (minocycline minimum inhibitory concentration (MIC) ≥16 μg/ml); which were resistant to at least three out of the following antibiotics: amikacin, ciprofloxacin, ceftazidime, gentamicin, meropenem, minocycline, piperacillin, piperacillin/tazobactam and tobramycin. Furthermore, the authors showed that loperamide (a μ-opioid receptor agonist, used as a gut anti-motility agent) showed synergy with eight different tetracycline antibiotics (chlortetracycline, democlocycline, doxycycline, minocycline, oxytetracycline, rolitetracycline, tetracycline and tigecycline), supporting that the synergistic effect of loperamide is related to its combination with the tetracycline antibiotic class. The combination of loperamide with the lipopeptide polymyxin B or ethylenediaminetetraacetic acid (EDTA), both of which disrupt the outer membrane, was also synergistic. Loperamide is purported to alter the permeability of the E. coli outer membrane for small molecules, not like the mechanism of action of the polymyxins [13,14]. Furthermore, the authors report that an additional screen for genetic enhancers of loperamide in combination with EDTA revealed an array of susceptible strains of E. coli with deletions in genes that function in lipopolysaccharide (LPS) biosynthesis, membrane transport and two-component signalling systems [5]. This would suggest that the synergistic activity of loperamide is partially due to its ability to target common pathways with EDTA, i.e. those that act to weaken the Gram-negative outer membrane.

Table 1
Reported antibiotic–non-antibiotic combinations for Gram-negatives
Non-antibiotic compoundChemical structurePharmacological activityApproved therapeutic useEffective against when in combination
Polymyxin B 
 
Curcumin [13,31 Natural product A. baumannii, E. coli, P. aeruginosa, Stenotrophomonas maltophilia, Enterococci, S. aureus and Streptococci 
Closantel [35 Anthelmintic Anthelmintic against multiple nematode species, veterinary use only A. baumannii 
Ivacaftor [41 Cystic fibrosis transmembrane conductance regulator channel (CFTR) potentiator Cystic fibrosis P. aeruginosa, K. pneumoniae, A. baumannii, S. maltophilia 
Tamoxifen [5357 Selective oestrogen receptor modulator (SERM) Advanced breast cancer, osteoporosis P. aeruginosa, K. pneumoniae, A. baumannii 
Raloxifen [5357 SERM Advanced breast cancer, osteoporosis P. aeruginosa, K. pneumoniae, A. baumannii 
Toremifen [5357 SERM Advanced breast cancer, osteoporosis P. aeruginosa, K. pneumoniae, A. baumannii 
Suloctidil [72 Vasodilator E. coli, Enterobacteriacae, H. influenzae, Mycobacteria, K. pneumoniae 
Zidovudine [73,74 Antiretroviral HIV E. coli, Enterobacteriacae, H. influenzae, Mycobacteria, K. pneumoniae 
Minocycline 
 
Benserazide [5 DOPA decarboxylase inhibitor Parkinson’s disease P. aeruginosa, S. aureus 
Chloroxine [5 Mitotic activity Antiseborrhoeic P. aeruginosa 
Tegaserod [5 5-HT receptor antagonist Irritable bowel syndrome P. aeruginosa, S. aureus 
Ascorbic Acid [5 Vitamin C, reducing agent, coenzyme, antioxidant Scurvy, vitamin C deficiency P. aeruginosa 
Mitomycin C [5 DNA-cross linking agent, antineoplastic antibiotic, alkylating, nucleic acid synthesis inhibitor Cancer P. aeruginosa, S. aureus 
Loperamide [5,13 Opioid-receptor agonist Acute and chronic diarrhoea P. aeruginosa 
Disulfiram [5 Alcohol dehydrogenase inhibitor Alcohol deterrent in abuse S. aureus 
Berberine [13 Traditional anti-diarrhoeic Diarrhoea Staphylococcal, Streptococcal and Enterococcal isolates 
Streptomycin 
 
Amlodipine [76 Ca2+ channel blocker Hypertension Salmonella typhimurium 
Ampicillin 
 
Verapamil [83 Ca2+ channel blocker Hypertension, angina, cluster headache prophylaxis E. coli, Staphylococcus epidermis 
Non-antibiotic compoundChemical structurePharmacological activityApproved therapeutic useEffective against when in combination
Polymyxin B 
 
Curcumin [13,31 Natural product A. baumannii, E. coli, P. aeruginosa, Stenotrophomonas maltophilia, Enterococci, S. aureus and Streptococci 
Closantel [35 Anthelmintic Anthelmintic against multiple nematode species, veterinary use only A. baumannii 
Ivacaftor [41 Cystic fibrosis transmembrane conductance regulator channel (CFTR) potentiator Cystic fibrosis P. aeruginosa, K. pneumoniae, A. baumannii, S. maltophilia 
Tamoxifen [5357 Selective oestrogen receptor modulator (SERM) Advanced breast cancer, osteoporosis P. aeruginosa, K. pneumoniae, A. baumannii 
Raloxifen [5357 SERM Advanced breast cancer, osteoporosis P. aeruginosa, K. pneumoniae, A. baumannii 
Toremifen [5357 SERM Advanced breast cancer, osteoporosis P. aeruginosa, K. pneumoniae, A. baumannii 
Suloctidil [72 Vasodilator E. coli, Enterobacteriacae, H. influenzae, Mycobacteria, K. pneumoniae 
Zidovudine [73,74 Antiretroviral HIV E. coli, Enterobacteriacae, H. influenzae, Mycobacteria, K. pneumoniae 
Minocycline 
 
Benserazide [5 DOPA decarboxylase inhibitor Parkinson’s disease P. aeruginosa, S. aureus 
Chloroxine [5 Mitotic activity Antiseborrhoeic P. aeruginosa 
Tegaserod [5 5-HT receptor antagonist Irritable bowel syndrome P. aeruginosa, S. aureus 
Ascorbic Acid [5 Vitamin C, reducing agent, coenzyme, antioxidant Scurvy, vitamin C deficiency P. aeruginosa 
Mitomycin C [5 DNA-cross linking agent, antineoplastic antibiotic, alkylating, nucleic acid synthesis inhibitor Cancer P. aeruginosa, S. aureus 
Loperamide [5,13 Opioid-receptor agonist Acute and chronic diarrhoea P. aeruginosa 
Disulfiram [5 Alcohol dehydrogenase inhibitor Alcohol deterrent in abuse S. aureus 
Berberine [13 Traditional anti-diarrhoeic Diarrhoea Staphylococcal, Streptococcal and Enterococcal isolates 
Streptomycin 
 
Amlodipine [76 Ca2+ channel blocker Hypertension Salmonella typhimurium 
Ampicillin 
 
Verapamil [83 Ca2+ channel blocker Hypertension, angina, cluster headache prophylaxis E. coli, Staphylococcus epidermis 

Polymyxin–non-antibiotic combinations

Polymyxin B and colistin (polymyxin E) are lipopeptide antibiotics indicated for the last-line treatment for MDR Gram-negative aerobic bacterial infections. Currently, only polymyxin B and colistin methane sulfonate (CMS), the prodrug of colistin, are used clinically [15]. The major constituents of clinical formulations of polymyxin B are 80% polymyxin B1, B2 and two minor constituents (B1-Ile7 and B3); colistin itself consists of ≥77% colistin A and B and three minor constituents [polymyxin E3, polymyxin E7 (7-methyloctanyl), E1-Ile7] [1618]. Polymyxins are cyclic heptapeptides consisting of five key domains: (i) the hydrophobic N-terminal fatty acyl chain, (ii) the linear tripeptide segment, (iii) five positively charged L-α,γ-diaminobutyric acid (Dab)-residues, (iv) a D-Phe/D-Leu-L-Leu hydrophobic motif at positions 6 and 7 and (v) the heptapeptide backbone [6]. The length of the N-terminal fatty acyl chain differs as follows: polymyxin B1 and colistin A possess a (S)-6-methyloctanoyl fatty acyl chain, whereas polymyxin B2 and colistin B display a shorter 6-methylheptanonyl fatty acyl chain [19]. Colistin and polymyxin B differ by a single amino acid within position 6 of the heptapeptide ring, colistin displays a D-leucine and polymyxin B displays a D-phenylalanine [20]. Polymyxins exert their antimicrobial action through a direct interaction with the lipid A component of the LPS causing disruption of the essential barrier function of the Gram-negative outer membrane [19]. Polymyxins zone into their primary cellular focus, LPS via an initial electrostatic interaction between the cationic Dab-residues with the negatively charged phosphate groups of the lipid A component of LPS, displacing divalent cations (Ca2+ and Mg2+) that bridge bordering LPS molecules, ensuing the disruption of the outer membrane barrier [19]. Secondary effects on inner membrane bacterial respiratory chain enzymes have also been reported [21].

Unfortunately, due to suboptimal use, various hospitals worldwide have reported the emergence of XDR Gram-negatives (including resistance to last-line polymyxins) which in essence means there are no effective treatment options available. The most common mechanism of resistance is through the modification of the lipid A phosphates with the positively charged sugar 4-amino-4-deoxy-L-arabinose (L-Ara-4-N) or phosphoethanolamine [6,2225]. The recent discovery of the widespread colistin resistance plasmid MCR-1 in Gram-negative isolates from humans and animals has rattled the cage for the long-term clinical utility of polymyxins in monotherapy [26]. To this end, a number of groups including ours have investigated the effectiveness of polymyxin–non-antibiotic combinations against Gram-negative ‘superbugs’.

Curcumin (a.k.a ‘Indian gold’) is a phenolic compound of the spice turmeric from the plant Curcuma longa Linn (Table 1). Curcumin has many beneficial pharmacological properties such as anti-tumour, anti-inflammatory and antioxidant activities and has been used as a natural therapeutic in Asia for centuries [2729]. Curcumin possesses a poor direct antimicrobial activity (MIC:125–1000 mg/l) against a broad spectrum of bacteria including E. coli, P. aeruginosa, Vibrio cholera and Bacillus subtilis [30]. However, Betts et al. [31] observed synergistic bacterial killing when combining curcumin with polymyxin B against a panel of Gram-negative isolates of A. baumannii, E. coli, P. aeruginosa and S. maltophilia and Gram-positive S. aureus and Streptococci bacteria isolated from nonsurgical traumatic wounds. Furthermore, the authors discovered that the polymyxin B–curcumin combination in a ratio of (43.4:1.5 μM) showed a decreased cytotoxicity in HaCaT keratinocyte cells [22%±3 pp (percentage points), P≤0.01] than treatment with curcumin alone [34%±2 pp at concentrations of 174 μM]. Encouragingly, the combination displayed synergy against polymyxin-resistant isolates and furthermore, expanded the spectrum of activity of polymyxin B to Gram-positive bacteria [31].

Although polymyxins are increasingly used for last-line therapy against A. baumannii, reports of polymyxin-resistant MDR strains are becoming more and more common [3234]. Recently, our group reported the antimicrobial synergy of polymyxin B in combination with the anthelmintic veterinary drug closantel, against a panel polymyxin-resistant and -susceptible isolates of A. baumannii. Closantel is an anthelmintic drug with direct activity against nematodes [35]. The anti-parasitic mode of action of closantel involves the uncoupling of oxidative phosphorylation and inhibition of chitinase [36,37]. Closantel treatment per se was ineffective against the A. baumannii isolates (MIC≥16 mg/l). Interestingly, the combination of closantel (4–16 mg/l) with the clinically relevant concentration of polymyxin B (2 mg/l) displayed synergistic antibacterial activity against polymyxin-resistant A. baumannii isolates and furthermore, successfully inhibited the emergence of resistance in polymyxin-susceptible isolates [38]. For A. baumannii, regrowth with polymyxin B or colistin monotherapy is largely driven partly by the amplification of polymyxin-resistant subpopulations, which highlights that caution is required for prolonged treatment using polymyxins alone [39,40].

Schneider et al. [41] reported synergistic antibacterial activity between polymyxin B in combination with the breakthrough cystic fibrosis (CF) drugs Kalydeco (ivacaftor) and Orkambi (ivacaftor + lumacaftor). The efficacy of the combinations was assessed against a panel of polymyxin-resistant and polymyxin-susceptible Gram-negatives CF isolates of P. aeruginosa, A. baumannii, K. pneumoniae, Burkholderia pseudomallei, Stenotrophomonas maltophilia and Haemophilus influenzae. P. aeruginosa commonly colonizes the lungs of adult CF patients and such infections are noted for being particularly recalcitrant towards antibiotic therapy [42]. Ivacaftor and lumacaftor are modulators of the CFTR [4346]. Polymyxin B, ivacaftor and lumacaftor per se were ineffective against polymyxin-resistant P. aeruginosa isolates (MIC≥4–128 mg/l). Intriguingly, the combination of clinically relevant concentrations of polymyxin B (2 mg/l) with Kalydeco (ivacaftor 8 mg/l) or Orkambi (ivacaftor 8 mg/l + lumacaftor 8 mg/l) displayed synergistic killing activity against polymyxin-resistant P. aeruginosa isolates, with a 100-fold decrease in bacterial count after 24 h. The Gram-negative outer membrane is a challenging barrier against hydrophobic drugs such as ivacaftor. As mentioned above, polymyxins utilize their antimicrobial action through direct interaction with the lipid A component of the LPS, which results in the disruption of the essential barrier function of the Gram-negative outer membrane [19]. Therefore, the underlying molecular basis for the synergistic activity of the combination may involve the capacity of polymyxin B to permeabilize the outer membrane, allowing ivacaftor to enter the cell and exert its antibacterial action against the intracellular targets (Figure 1).

Schematic depicting one putative mechanism of synergistic activity for polymyxin–non-antibiotic drug combinations against Gram-negative bacteria

Figure 1
Schematic depicting one putative mechanism of synergistic activity for polymyxin–non-antibiotic drug combinations against Gram-negative bacteria

FDA-approved non-antibiotics fail to cross the Gram-negative outer membrane, for example, due to high hydrophobicity, and cannot reach their intracellular targets. The molecular basis for the synergistic activity involves the ability of the polymyxin to permeabilize the outer membrane thereby allowing the non-antibiotic to enter the cell and exert its antimicrobial action on intracellular targets. Alternatively, the non-antibiotic could synergize with the polymyxin by exerting a concerted outer membrane disrupting effect.

Figure 1
Schematic depicting one putative mechanism of synergistic activity for polymyxin–non-antibiotic drug combinations against Gram-negative bacteria

FDA-approved non-antibiotics fail to cross the Gram-negative outer membrane, for example, due to high hydrophobicity, and cannot reach their intracellular targets. The molecular basis for the synergistic activity involves the ability of the polymyxin to permeabilize the outer membrane thereby allowing the non-antibiotic to enter the cell and exert its antimicrobial action on intracellular targets. Alternatively, the non-antibiotic could synergize with the polymyxin by exerting a concerted outer membrane disrupting effect.

As the chemical structure of ivacaftor bears resemblance to the quinolones (Table 1), it is possible that the antibacterial activity of ivacaftor is due to a quinolone-like antimicrobial mode of action. The antibacterial mode of action of quinolone antibiotics involves the inhibition of the related DNA gyrase and topoisomerase IV enzymes that play a key role in DNA replication [47]. Schneider et al. [41] showed that ivacaftor is a weak catalytic inhibitor of the bacterial DNA gyrase and topoisomerase IV enzymes, but does not have interfacial poisoning activity. The deficiency of enzyme inhibition by ivacaftor was interpreted in terms of quinolone structure–activity relationships (SAR). Firstly, ivacaftor has a bulky N-(2,4-di-tert-butyl-5-)hydroxyphenyl substituting R3 of the quinolone nucleus in the place of the carboxylic acid (Table 1), which results in the inactivation of quinolone antibacterial activity [47]. Secondly, the ivacaftor structure essentially contains a bare quinolone nucleus, which is missing the fundamental substituents at the R1, R6 and R7 substituents that are critical for binding to the enzyme–DNA complex [47]. In summary, the combination of polymyxin B with ivacaftor offers novel treatment options for otherwise untreatable P. aeruginosa CF lung infections [41].

SERMs such as tamoxifen, raloxifene and toremifene are used for the treatment of advanced breast cancer and osteoporosis in pre- and post-menopausal women [4851]. Hussein et al. [52] have found that clinically relevant concentrations of polymyxin B in combination with the aforementioned SERMs display excellent synergy against XDR polymyxin-resistant (MIC≥8 mg/l) P. aeruginosa, K. pneumoniae and A. baumannii. The combinations produced a ≥2–3 log10 decrease in bacterial count (CFU/ml) after 24 h, whereas, monotherapy with each drug was ineffective. SERMs have been reported to display direct antifungal, antiviral and antiparasitic activities [5357]. To probe whether the synergy between polymyxin B and the SERMs is a result of the permeabilizing activity of polymyxin on the Gram-negative outer membrane that allows the SERMs to enter the cells and reach their intracellular targets the authors examined whether polymyxin nonapeptide in combination with tamoxifen was synergistic against P. aeruginosa. Polymyxin nonapeptide has the N-terminal fatty acyl-Dab1 segment removed and consequently lacks the direct bactericidal activity of the mature polymyxin molecule, albeit, it retains the outer membrane permeabilizing activity and is often employed as a sensitizer for other antibiotics [58]. The polymyxin nonapeptide–tamoxifen combination was inactive against the two polymyxin resistant P. aeruginosa strains tested whereas good synergy (FIC=0.18) was observed against the polymxyin susceptible P. aeruginosa ATCC 278853. SERMs are known to be membrane-active drugs [5962]. For example, tamoxifen has been shown to interact with lipids in biomembranes and cause ultrastructural changes potentially resulting in cell lysis [60,63]. Additional effects of tamoxifen suggesting its direct action on biomembranes include its ability to alter the morphology of the breast tumour cell membranes [60]; and other biomembrane-related effects including haemolysis [61], mitochondrial swelling [64] and proton leakage from the mitochondrial inner membrane resulting in depolarization of membrane potential [65,66]. It is therefore tenable to imagine that the synergistic antibacterial activity of polymxyin B combined with SERMs results from their combined action against the Gram-negative outer membrane (Figure 1). Taking into account that this synergistic mechanism could also potentially act synergistically to increase toxicity, the authors have performed experiments that demonstrated polymyxin B is not haemolytic even at very high concentrations >128 mg/l, which are certainly not clincally relevant [67]. Furthermore, a number of clinical studies have shown that very high toremifene and tamoxifen doses (up to 240 mg/day) are well tolerated [6871]. Therefore, increased toxicity of this combination does not seem to be an issue at the clincally relevant concentrations of each drug used in our study.

In 2016, Helperby Therapeuticals Limited issued a patent (WO 2016/097754 A1) combining the vasodilator suloctidil in combination with polymyxins [72]. They showed that suloctidil (4, 8 or 16 mg/l) and colistin (1, 2, 4 and 8 mg/l) per se showed no antibacterial activity against NDM-1 E. coli whereas when in combination a synergistic antibacterial effect was evident. Furthermore, the company holds other patents (WO 2015/114340 A1) combining rifampicin or zidovudine with colistin [73] or with polymyxin B [74]. They have found that administration of rifampicin, colistin or zidovudine alone showed no in vivo activity against the NDM-1 K. pneumoniae [73]. Both combinations produced a 3.1 log10 kill (rifampicin–zidovudine combination), 4.1 log10 (colistin–zidovudine combination) and 4.6 log10 (rifampicin–colistin–zidovudine triple combination).

Other promising combinations

The isoquinoline alkaloid berberine, found in various plants, i.e. the roots and rhizome of Berberis has an ancient history of use for numerous conditions such as the treatment of diarrhoea caused by the parasite Giardia lamblia as well as Gram-negative infections [13]. Berberine has been reported to have a broad-spectrum antibacterial activity against Staphylococcal, Streptococcal and Enterococcal isolates [13]. Yu et al. [75] reported that berberine noticeably lowered the MIC of ampicillin (additive effect) and oxacillin (synergistic effect) against methicillin-resistant S. aureus (MRSA). The authors purport that berberine may possess direct antimicrobial activity and possibly the potential to restore the effectiveness of β-lactam antibiotics against MRSA [75].

A number of in vitro and in vivo studies with cardiovascular drugs such as amlodipine, dobutamine, lacidipine, nifedipine and oxyfedrine have shown that these compounds possess antibacterial activity [7680]. Amlodipine, a dihydropyridine Ca2+ channel blocker, prescribed for the treatment of hypertension, displayed antibacterial activity against Listeria, Staphylococcus, Bacillus, Shigella and Vibrio [76]. Furthermore, when used in combination with streptomycin, amlodipine showed synergistic antibacterial activity in a mouse model against S. typhimurium (P<0.001) [81]. The antipsychotic drugs prochlorperazine, chlorpromazine and promazine have been shown to act synergistically with the aminoglycosides and macrolide antibiotics against Burkholderia pseudomallei [82]. In addition, Gunics et al. [83] showed that the combination of the neuroleptic promethazine with either ampicillin or tetracycline displayed synergistic antibacterial activity against E. coli or with erythromycin against both E. coli and S. epidermis [83]. Furthermore, these authors showed that verapamil displayed synergistic antibacterial activity in combination with ampicillin against E. coli and S. epidermis.

Perspective

In summary, our review highlights the potential clinical utility of combining non-antibiotic FDA-approved drugs with antibiotics such as polymyxin B and minocycline for the treatment of XDR bacterial infections. P. aeruginosa in particular is intrinsically resistant to antibiotics, and is noted as requiring an urgent need for new anti-pseudomonal therapeutic options [84]. Because existing drugs have known pharmacokinetic and safety profiles and have already acquired approval for human use from regulatory agencies, combinations of these ‘old’ drugs could be fast-tracked into the clinic [8,85]. From a practical standpoint, this literature review suggests that these FDA-approved non-antibiotics represent a potentially novel reservoir of novel anti-infectives that could prove to be of considerable utility for antibiotic drug design and for tailoring ‘old’ compounds. Combining non-antibiotics with antibiotics has developed into a promising and emerging area of the anti-infectives field. However, this review only scratches the surface of this potential gold-mine of novel and innovating anti-infective therapies.

Summary

  • The emergence of antimicrobial resistance of Gram-negative pathogens has become a world-wide crisis.

  • Combining antibiotics with FDA-approved non-antibiotic drugs has emerged as a novel approach to combat otherwise untreatable infections.

  • Loperamide, a µ-opioid receptor agonist, showed synergy against with eight tetracycline antibiotics including minocycline and the lipopeptide polymyxin B.

  • Lipopeptide antibiotics (polymyxin B and colistin) displayed synergistic antibacterial activity in combination with curcumin (spice), closantel (anthelmintic), ivacaftor and lumacaftor (cystic fibrosis drugs), tamoxifen, raloxifene and toremifene (selective estrogen receptor modulators), suloctidil (vasodilator) and zidovudine (antiretroviral drug).

Funding

J.L. and T.V. are supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health [R01 AI111965]. (The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.) E.K.S. is supported by an Australian Postgraduate Award (APA). J.L. is an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellow. T.V. is an Australian NHMRC Career Development Research Fellow.

Competing interests

The Authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • CF

    cystic fibrosis

  •  
  • CFTR

    cystic fibrosis transmembrane conductance regulator channel

  •  
  • CFU

    colony forming unit

  •  
  • Dab

    l-α-γ-diaminobutyric acid

  •  
  • FDA

    Food and Drug Administration

  •  
  • DOPA

    3,4-dihydroxyphenylalanine

  •  
  • FIC

    fractional inhibitory concentration

  •  
  • 5-HT

    serotonin (5-hydroxytryptamine)

  •  
  • LPS

    lipopolysaccharide

  •  
  • MDR

    multidrug-resistant

  •  
  • MIC

    minimum inhibitory concentration

  •  
  • MRSA

    methicillin-resistant S. aureus

  •  
  • NDM-1

    New Delhi metallo-β-lactamase 1

  •  
  • pp

    percentage points

  •  
  • SERM

    selective oestrogen receptor modulator

  •  
  • XDR

    extremely drug-resistant

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