Concern over antibiotic resistance is growing. Resistance of up to 50% has been reported in some regions, including resistance to carbapenems, our current last line of defence.
New classes of antibiotics are needed, particularly against Gram-negative bacteria. However, even if the scientific hurdles can be overcome, it could take decades before sufficient numbers of such antibiotics become available.
As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics.
Several marketed drugs that do not currently have antibacterial indications can directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics, modulate host defence through effects on host innate immunity, particularly inflammation and autophagy, or a combination of these three.
This article discusses how such 'antibiotic resistance breakers' (ARBs) could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation.
Concern over antibiotic resistance is growing, and new classes of antibiotics, particularly against Gram-negative bacteria, are needed. However, even if the scientific hurdles can be overcome, it could take decades for sufficient numbers of such antibiotics to become available. As an interim solution, antibiotic resistance could be 'broken' by co-administering appropriate non-antibiotic drugs with failing antibiotics. Several marketed drugs that do not currently have antibacterial indications can either directly kill bacteria, reduce the antibiotic minimum inhibitory concentration when used in combination with existing antibiotics and/or modulate host defence through effects on host innate immunity, in particular by altering inflammation and autophagy. This article discusses how such 'antibiotic resistance breakers' could contribute to reducing the antibiotic resistance problem, and analyses a priority list of candidates for further investigation.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Rice, L. B. Federal funding for the study of antimicrobial resistance in nosocomial pathogens: no ESKAPE. J. Infect. Dis. 197, 1079–1081 (2008).
Woodford, N., Wareham, D. W., Guerra, B. & Teale, C. Carbapenemase-producing Enterobacteriaceae and non-Enterobacteriaceae from animals and the environment: an emerging public health risk of our own making? J. Antimicrob. Chemother. 69, 287–291 (2014).
Davis, S. C. Infections and the rise of antimicrobial resistance. UK Government [online], (2015)
Centers for Disease Contol and Prevention. Antibiotic resistance threats in the United States, 2013. CDC [online], (2013).
Bassetti, M. & Righi, E. Eravacycline for the treatment of intra-abdominal infections. Expert Opin. Investigat. Drugs 23, 1575–1584 (2014).
Walkty, A. et al. In vitro activity of plazomicin against 5015 Gram-negative and Gram-positive clinical isolates obtained from patients in Canadian hospitals as part of the CANWARD study, 2011–2012. Antimicrob. Agents Chemother. 58, 2554–2563 (2014).
Zhanel, G. G. et al. Ceftazidime–avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs. 73, 159–177 (2013).
Zhanel, G. G. et al. Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs. 74, 31–51 (2014).
White, A. R. et al. Augmentin (amoxicillin/clavulanate) in the treatment of community-acquired respiratory tract infection: a review of the continuing development of an innovative antimicrobial agent. J. Antimicrob. Chemother. 53 (Suppl. 1), i3–i20 (2004).
Prabhudesai, P. P. et al. The efficacy and safety of amoxicillin-clavulanic acid 1000/125mg twice daily extended release (XR) tablet for the treatment of bacterial community-acquired pneumonia in adults. J. Indian Med. Assoc. 109, 124–127 (2011).
Coates, A. & Hu, Y. in Novel Antimicrobial Agents and Strategies Ch. 2 (eds Phoenix, D. A., Harris, F. & Dennison, S. R.) (Wiley, 2014).
Blair, J. M., Richmond, G. E. & Piddock, L. J. Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol. 9, 1165–1177 (2014).
Amsden, G. W. Anti-inflammatory effects of macrolides — an under-appreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J. Antimicrob. Chemother. 55, 10–21 (2005).
Kudoh, S. et al. Improvement of survival in patients with diffuse panbronchiolitis treated with low dose erythromycin. Amer. J. Resp. Crit. Care Med. 157, 1829–1832 (1998).
Kudoh, S. et al. Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 25, 632–642 (in Japanese) (1987).
Tateda, K. et al. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 45, 1930–1933 (2001).
Molinari, G. et al. Inhibition of Pseudomonas aeruginosa virulence factors by subinhibitory concentrations of azithromycin and other macrolide antibiotics. J. Antimicrob. Chemother. 31, 681–688 (1993).
Nguyen, T. et al. Potential role of macrolide antibiotics in the management of cystic fibrosis lung disease. Curr. Opin. Pulmonary Med. 8, 521–528 (2002).
Karabay, O. et al. A new effect of acetylsalicylic acid? Significantly lower prevalence of nasal carriage of Staphylococcus aureus among patients receiving orally administered acetylsalicylic acid. Infect. Control Hosp. Epidemiol. 27, 318–319 (2006).
Sedlacek, M. et al. Aspirin treatment is associated with a significantly decreased risk of Staphylococcus aureus bacteremia in hemodialysis patients with tunneled catheters. Am. J. Kidney Dis. 49, 401–408 (2007).
Mazumdar, K. et al. Diclofenac in the management of E. coli urinary tract infections. In Vivo 20, 613–619 (2006).
Mazumdar, K. et al. The anti-inflammatory non-antibiotic helper compound diclofenac: an antibacterial drug target. Eur. J. Clin. Microbiol. Infect. Dis. 28, 881–891 (2009).
Pongkorpsakol, P. et al. Inhibition of cAMP-activated intestinal chloride secretion by diclofenac: cellular mechanism and potential application in cholera. PLoS Negl. Trop. Dis. 8, e3119 (2014).
Vilaplana, C. et al. Ibuprofen therapy resulted in significantly decreased tissue bacillary loads and increased survival in a new murine experimental model of active tuberculosis. J. Infect. Dis. 208, 199–202 (2013).
Eisen, D. P. et al. Low-dose aspirin and ibuprofen sterilizing effects on Mycobacterium tuberculosis suggest safe new adjuvant therapies for tuberculosis. J. Infect. Diseases 208, 1925–1927 (2013).
Cicerale, S., Lucas, L. J. & Keast, R. S. Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil. Curr. Opin. Biotechnol. 23, 129–135 (2012).
Pettengill, M. et al. Ivermectin inhibits growth of Chlamydia trachomatis in epithelial cells. PLoS ONE 7, e48456 (2012).
Zhang, X. et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm. Res. 57, 524–529 (2008).
Schlievert, P. M. et al. Effect of glycerol monolaurate on bacterial growth and toxin production. Antimicrob. Agents Chemother. 36, 626–631 (1992).
Projan, S. J. et al. Glycerol monolaurate inhibits the production of β-lactamase, toxic shock syndrome toxin-1, and other staphylococcal exoproteins by interfering with signal transduction. J. Bacteriol. 176, 4204–4209 (1994).
Zhao, X. et al. Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury. Am. J. Physiol. Lung Cell. Mol. Physiol. 295, 497–504 (2008).
Tsoyi, K. et al. Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br. J. Pharmacol. 162, 1498–1508 (2010).
Rogers, A. C. et al. Activation of AMPK inhibits cholera toxin stimulated chloride secretion in human and murine intestine. PLoS ONE 8, e69050 (2013).
Yuk, J. M. et al. Vitamin D3 induces autophagy in human monocytes/ macrophages via cathelicidin. Cell Host Microbe 6, 231–234 (2009).
Montoya, D. et al. IL-32 is a molecular marker of a host defense network in human tuberculosis. Sci. Transl. Med. 20, 250 (2014).
Dittmar, W. et al. Microbiological laboratory studies with ciclopiroxolamine. Drug Res. 31, 1317–1322 (1981).
Carlson-Banning, K. M. et al. Toward repurposing Ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. PLoS ONE 8, e69646 (2013).
Niewerth, M. et al. Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors. Antimicrob. Agents Chemother. 47, 1805–1817 (2003).
Dihazi, G. H. et al. Impact of the antiproliferative agent ciclopirox olamine treatment on stem cells proteome. World J. Stem Cells 5, 9–25 (2013).
Zhou, H. et al. Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway. Oncotarget 5, 10140–10150 (2014).
Weir, S. J. et al. The repositioning of the anti-fungal agent ciclopirox olamine as a novel therapeutic agent for the treatment of haematologic malignancy. J. Clin. Pharm. Ther. 36, 128–134 (2011).
Eberhard, Y. et al. Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood 114, 3064–3073 (2009).
Kellner, H. M. et al. Pharmacokinetics and biotransformation of the antimycotic drug ciclopiroxolamine in animals and man after topical and systemic administration. Arzneimittelforschung 31, 1337–1353 (in German) (1981).
Minden, M. D. et al. Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies. Am. J. Hematol. 89, 363–368 (2014).
Ejim, L. et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat. Chem. Biol. 7, 348–350 (2011).
Taylor. P. L. et al. A forward chemical screen identifies antibiotic adjuvants in Escherichia coli. ACS Chem. Biol. 7, 1547–1555 (2012).
Tascini, C. et al. Synergistic activity of colistin plus rifampin against colistin-resistant KPC-producing Klebsiella pneumoniae. Antimicrob. Agents Chemother. 57, 3990–3993 (2013).
Yu, H.-H. et al. Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. J. Med. Food 8, 454–461 (2005).
Kim, S.-H. et al. Inhibition of the bacterial surface protein anchoring transpeptidase sortase by isoquinoline alkaloids. Biosci. Biotechnol. Biochem. 68, 421–424 (2004).
Domadia, P. N. Berberine targets assembly of Escherichia coli cell division protein FtsZ. Biochemistry 47, 3225–3234 (2008).
Chu, M. et al. Role of berberine in anti-bacterial as a high-affinity LPS antagonist binding to TLR4/MD-2 receptor. BMC Complement. Altern. Med. 14, 89 (2014).
Jin, J. L. et al. Antibacterial mechanisms of berberine and reasons for little resistance of bacteria. Chinese Herbal Med. 3, 27–35 (2010).
Li, H.-M. et al. Berberine protects against lipopolysaccharide-induced intestinal injury in mice via α 2 adrenoceptor-independent mechanisms. Acta Pharmacol. Sin. 32, 1364–1372 (2011).
Jeong, H. W. et al. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am. J. Physiol. Endocrinol. Metab. 296, 955–964 (2009).
Zhang, M. & Chen, L. Berberine in type 2 diabetes therapy: a new perspective for an old antidiarrheal drug? Acta Pharmaceutica Sinica B 2, 379–386 (2012).
Zhang, H. et al. Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism 59, 285–292 (2009).
Yin, J., Xing, H. & Ye, J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism 57, 712–717 (2008).
Fürst, R. & Zündorf, I. Plant-derived anti-inflammatory compounds: hopes and disappointments regarding the translation of preclinical knowledge into clinical progress. Mediators Inflamm. 2014, 146832 (2014).
Gupta, S. C., Patchva, S. & Aggarwal, B. B. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 15, 195–218 (2013).
Moghadamtousi, S. Z. et al. A review on antibacterial, antiviral, and antifungal activity of curcumin. Biomed. Res. Int. 186864 (2014).
Mahady, G. B. et al. Turmeric (Curcuma longa) and curcumin inhibit the growth of Helicobacter pylori, a group 1 carcinogen. Anticancer Res. 22 4179–4181 (2002).
De, R. et al. Antimicrobial activity of curcumin against Helicobacter pylori isolates from India and during infections in mice. Antimicrob. Agents Chemother. 53, 1592–1597 (2009).
Aljamal, A. Effect of turmeric in peptic ulcer and H pylori. Plant Sci. Res. 3, 25–28 (2011).
Di Mario, F. et al. A curcumin-based 1-week triple therapy for eradication of Helicobacter pylori infection: something to learn from failure? Helicobacter 12, 238–243 (2007).
Koosirirat, C. et al. Investigation of the antiinflammatory effect of Curcuma longa in Helicobacter pylori-infected patients. Int. Immunopharmacol. 10, 815–818 (2010).
Patel, R. & Yang, N. Inhibiting hospital associated infection of toxigenic Clostridium difficile using natural spice-turmeric (curcumin). Amer. J. Gastroenterol. 105, S122–S122 (2010).
Sasidharan, N. K. et al. In vitro synergistic effect of curcumin in combination with third generation cephalosporins against bacteria associated with infectious diarrhea. Biomed. Res. Int. 2014, 561456 (2014).
Moghaddam, K. M. et al. The combination effect of curcumin with different antibiotics against Staphylococcus aureus. Int. J. Green Pharm. 3, 141–143 (2009).
Mun, S. H. et al. Synergistic antibacterial effect of curcumin against methicillin-resistant Staphylococcus aureus. Phytotherapy Research 19, 599–604 (2013).
Park, B. S. et al. Curcuma longa L. constituents inhibit sortase A and Staphylococcus aureus cell adhesion to fibronectin. J. Agr. Food Chem. 53, 9005–9009 (2005).
Aoki, H. et al. Evidence that curcumin suppresses the growth of malignant gliomas in vitro and in vivo through induction of autophagy: role of Akt and extracellular signal-regulated kinase signaling pathways. Mol. Pharmacol. 72, 29–39 (2007).
Gradisar, H. et al. MD-2 as the target of curcumin in the inhibition of response to LPS. J. Leukocyte Biol. 82, 968–974 (2007).
Tu, X.-K. et al. Curcumin inhibits TLR2/4-NF-κB signaling pathway and attenuates brain damage in permanent focal cerebral ischemia in rats. Inflammation 37, 1544–1551 (2014).
Shuto, T. et al. Curcumin decreases toll-like receptor-2 gene expression and function in human monocytes and neutrophils. Biochem. Biophys. Res. Commun. 398, 647–652 (2010).
Tu, C.-T. et al. Curcumin attenuates concanavalin A-induced liver injury in mice by inhibition of Toll-like receptor (TLR) 2, TLR4 and TLR9 expression. Intnl Immunopharmacol. 12, 151–157 (2012).
Chan, M. M. Inhibition of tumor necrosis factor by curcumin, a phytochemical. Biochem. Pharmacol. 49, 1551–1556 (1995).
Chainani-Wu, N. Safety and anti-inflammatory activity of curcumin: a component of tumeric (Curcuma longa). J. Altern. Compl. Med. 9, 161–168 (2003).
Bengmark, S. Curcumin, an atoxic antioxidant and natural NFκB, cyclooxygenase-2, lipooxygenase, and inducible nitric oxide synthase inhibitor: a shield against acute and chronic diseases. J. Parenteral Enteral Nutr. 30, 45–51 (2006).
Jain, S. K. et al. Curcumin supplementation lowers TNF-α, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-α, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxid. Redox Signal. 11, 241–249 (2009).
Hansen, E. et al. A versatile high throughput screening system for the simultaneous identification of anti-inflammatory and neuroprotective compounds. J. Alzheimer's Disease 19, 451–464 (2010).
Ryan, A. et al. A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins. PLoS Pathog. 7, e1002076 (2011).
Pothoulakis, C. Effects of Clostridium difficile toxins on epithelial cell barrier. Ann. NY Acad. Sci. 915, 347–356 (2000).
Sintara, K. et al. Curcumin suppresses gastric NF-κB activation and macromolecular leakage in Helicobacter pylori-infected rats. World J. Gastroenterol. 16, 4039–4046 (2010).
Brennan, P. & O'Neill, L. A. Inhibition of nuclear factor κB by direct modification in whole cells — mechanism of action of nordihydroguaiaritic acid, curcumin and thiol modifiers. Biochem. Pharmacol. 55, 965–973 (1998).
Steiner, T. S. et al. Faecal lactoferrin, interleukin 1b, and interleukin-8 are elevated in patients with severe Clostridium difficile colitis. Clin. Diagn. Lab. Immunol. 4, 719–722 (1997).
Jafari, N. V. et al. Clostridium difficile modulates host innate immunity via toxin-independent and dependent mechanism(s). PLoS ONE 8, e69846 (2013).
Rao, K. et al. The systemic inflammatory response to Clostridium difficile infection. PLoS ONE 9, e92578 (2014).
Feghaly, R. et al. Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin. Infect. Dis. 56, 1713–1721 (2013).
Basu, P. P. et al. Turmeric enema: a novel therapy for C. difficile colitis (CDAD): A randomized, double blinded, placebo controlled prospective clinical trial. Internat. J. Infectious Diseases 15 (Suppl. 15), S39 (2011).
Sharma, R. A. et al. Pharmacodynamic and pharmacokinetic study of oral curcuma extract in patients with colorectal cancer. Clin. Cancer Res. 7, 1894–1900 (2001).
Lim, G. P. et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J. Neurosci. 21, 8370–8377 (2001).
Begum, A. N. et al. Curcumin structure function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease. J. Pharmacol. Exp. Ther. 326, 196–208 (2008).
Yang, F. et al. Curcumin inhibits formation of amyloid-β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 280, 5892–5901 (2005).
McNaught, J. On the action of cold or lukewarm tea on Bacillus typhosus. J. R. Army Med. Corps 7, 372–373 (1906).
Steinmann, J. et al. Anti-infective properties of epigallocatechin-3-gallate (EGCG), a component of green tea. Br. J. Pharmacol. 168, 1059–1073 (2013).
Wolska, K. I., Grzes´, K. & Kurek, A. Synergy between novel antimicrobials and conventional antibiotics or bacteriocins. Pol. J. Microbiol. 61, 95–104 (2012).
Yam, T. S., Hamilton-Miller, J. M. & Shah S. The effect of a component of tea (Camellia sinensis) on methicillin resistance, PBP2′ synthesis, and β-lactamase production in Staphylococcus aureus. J. Antimicrob. Chemother. 42, 211–216 (1998).
Stapleton, P. D. et al. Modulation of β-lactam resistance in Staphylococcus aureus by catechins and gallates. Int. J. Antimicrob. Agents 23, 462–467 (2004).
Zhao, W. et al. Mechanism of synergy between epigallocatechin gallate and β-lactams against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 45, 1737–1742 (2001).
Hu, Z.-Q. et al. Epigallocatechin gallate synergy with ampicillin/sulbactam against 28 clinical isolates of methicillin-resistant Staphylococcus aureus. J. Antimicrob. Chemother. 48, 361–364 (2001).
Hu, Z.-Q. et al. Epigallocatechin gallate synergistically enhances the activity of carbapenems against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 46, 558–560 (2002).
Navarro-Martinez, M. D. et al. Antifolate activity of epigallocatechin gallate against Stenotrophomonas maltophilia. Antimicrob. Agents Chemother. 49, 2914–2920 (2005).
Lee, H. C. et al. Effect of tea phenolics and their aromatic fecal bacterial metabolites on intestinal microbiota. Res. Microbiol. 157, 876–884 (2006).
Reygaert, W. & Jusufi, I. Green tea as an effective antimicrobial for urinary tract infections caused by Escherichia coli. Front. Microbiol. 4, 162 (2013).
Li, W. et al. A major ingredient of green tea rescues mice from lethal sepsis partly by inhibiting HMGB1. PLoS ONE 2, e1153 (2007).
Zhao, W.-H. et al. Inhibition of penicillinase by epigallocatechin gallate resulting in restoration of antibacterial activity of penicillin against penicillinase-producing Staphylococcus aureus. Antimicrob. Agents Chemother. 46, 2266–2268 (2002).
Stapleton, P. D. et al. The β-lactam-resistance modifier (−)-epicatechin gallate alters the architecture of the cell wall of Staphylococcus aureus. Microbiology 153, 2093–2103 (2007).
Grandišar, H. et al. Green tea catechins inhibit bacterial DNA gyrase by interaction with its ATP binding site. J. Med. Chem. 50, 264–271 (2007).
Zhang, Y. M. & Rock, C. O. Evaluation of epigallocatechin gallate and related plant polyphenols as inhibitors of the FabG and FabI reductases of bacterial type II fatty-acid synthesis. J. Biol. Chem. 279, 30994–31001 (2004).
Lee, K. M. et al. Protective mechanism of epigallocatechin-3-gallate against Helicobacter pylori-induced gastric epithelial cytotoxicity via the blockage of TLR-4 signaling. Helicobacter 9, 632–642 (2004).
Zhao, W. H. et al. Inhibition by epigallocatechin gallate (EGCG) of conjugative R plasmid transfer in Escherichia coli. J. Infect. Chemother. 7, 195–197 (2001).
Sudano Roccaro, A. et al. Epigallocatechin-gallate enhances the activity of tetracycline in staphylococci by inhibiting its efflux from bacterial cells. Antimicrob. Agents Chemother. 48, 1968–1973 (2004).
Li, W. et al. EGCG stimulates autophagy and reduces cytoplasmic HMGB1 levels in endotoxin-stimulated macrophages. Biochem. Pharmacol. 81, 1152–1163 (2011).
Kim, H. S. et al. Epigallocatechin gallate (EGCG) stimulates autophagy in vascular endothelial cells: a potential role for reducing lipid accumulation. J. Biol. Chem. 288, 22693–22705 (2013).
Zhou, J. et al. Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance. PLoS ONE 9, e87161 (2014).
Ullmann, U. et al. A single ascending dose study of epigallocatechin gallate in healthy volunteers. J. Int. Med. Res. 31, 88–101 (2003).
Lambert, J. D. et al. Peracetylation as a means of enhancing in vitro bioactivity and bioavailability of epigallocatechin-3-gallate. Drug Metab. Dispos. 34, 2111–2116 (2006).
Matsumoto, Y. et al. Antibacterial and antifungal activities of new acylated derivatives of epigallocatechin gallate. Front. Microbiol. 3, 53 (2012).
Hutchinson, M. R. et al. Evidence that opioids may have toll like receptor 4 and MD-2 effects. Brain Behav. Immun. 24, 83–95 (2010).
Hutchinson, M. R. et al. Opioid activation of toll-like receptor 4 contributes to drug reinforcement. J. Neurosci. 32, 11187–11200 (2012).
Dawson, A. in Medical Toxicology 3rd edn (ed. Dart, R.) 228–230 (Lippincott, Williams and Wilkins, 2004).
Clifton, L. A. et al. Effect of divalent cation removal on the structure of Gram-negative bacterial outer membrane models. Langmuir 31, 404–412 (2015).
Gill, E. E., Franco, O. L. & Hancock, R. E. Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens. Chem. Biol. Drug Des. 85, 56–78 (2015).
Chauhan, A. et al. Full and broad-spectrum in vivo eradication of catheter-associated biofilms using gentamicin-EDTA antibiotic lock therapy. Antimicrob. Agents Chemother. 56, 6310–6318 (2012).
Deretic, V. Autophagy in immunity and cell-autonomous defense against intracellular microbes. Immunol. Rev. 240, 92–104 (2011).
Campoy, E. & Colombo, M. I. Autophagy in intracellular bacterial infection. Biochim. Biophys. Acta 1793, 1465–1477 (2009).
Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004).
Birmingham, C. L. et al. Autophagy controls salmonella infection in response to damage to the salmonella-containing vacuole. J. Biol. Chem. 281, 11374–11383 (2006).
Ogawa, M. et al. Escape of intracellular Shigella from autophagy. Science 307, 727–731 (2005).
Yano, T. et al. Autophagic control of Listeria through intracellular innate immune recognition in drosophila. Nat. Immunol. 9, 908–916 (2008).
Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).
Amano, A., Nakagawa, I. & Yoshimori, T. Autophagy in innate immunity against intracellular bacteria. J. Biochem. 140, 161–166 (2006).
Vergne, I. et al. Autophagy in immune defense against Mycobacterium tuberculosis. Autophagy 2, 175–178 (2006).
Mostowy, S. Autophagy and bacterial clearance: a not so clear picture. Cell. Microbiol. 15, 395–402 (2013).
Kuballa, P. et al. Autophagy and the immune system. Annu. Rev. Immunol. 30, 611–646 (2012).
Levine, B., Mizushima, N. & Virgin, H. W. Autophagy in immunity and inflammation. Nature 469, 323–335 (2011).
Poels, J. et al. Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. Bioessays 31, 944–952 (2009).
Inoki, K. et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126, 955–968 (2006).
Ulgherait, M. et al. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 8, 1767–1780 (2014).
Wang, W. H. et al. Aspirin inhibits the growth of Helicobacter pylori and enhances its susceptibility to antimicrobial agents. Gut 52, 490–495 (2003).
Price, C. T. et al. The effects of salicylate on bacteria. Internat. J. Biochem. Cell Biol. 32, 1029–1043 (2000).
Nicolau, D. P. et al. Influence of aspirin on development and treatment of experimental Staphylococcus aureus endocarditis. Antimicrob. Agents Chemother. 39, 1748–1751 (1995).
Nicolau, D. P. et al. Reduction of bacterial titers by low-dose aspirin in experimental aortic valve endocarditis. Infect. Immun. 61, 1593–1595 (1993).
Dutta, N. K. et al. The anti-inflammatory drug diclofenac retains anti-listerial activity in vivo. Lett. Appl. Microbiol. 47, 106–111 (2008).
Dutta, N. K. et al. Potential management of resistant microbial infections with a novel non-antibiotic: the anti-inflammatory drug diclofenac sodium. Int. J. Antimicrob. Agents 30, 242–249 (2007).
Dutta, N. K. et al. Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice. Int. J. Antimicrob. Agents 30, 336–340 (2007).
Zhang, X. et al. Inhibitory effects of ivermectin on nitric oxide and prostaglandin E2 production in LPS-stimulated RAW 264.7 macrophages. Int. Immunopharmacol. 9, 354–359 (2009).
Bae, H.-B. et al. AMP-activated protein kinase enhances the phagocytic ability of macrophages and neutrophils. FASEB J. 25, 4358–4368 (2011).
Singhal, A. et al. Metformin as adjunct antituberculosis therapy. Sci. Transl. Med. 6, 263ra159 (2014).
Maeurer, M. & Zumla, A. The host battles drug-resistant tuberculosis. Sci. Transl. Med. 6, 263fs47 (2014).
Salahuddin, N. et al. Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study [Supplementary Cholecalciferol in recovery from tuberculosis]. A randomized, placebo-controlled clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis. BMC Infect. Dis. 13, 22 (2013).
Anand, P. K. & Kaul, D. Vitamin D3-dependent pathway regulates TACO gene transcription. Biochem. Biophys. Res. Commun. 310, 876–877 (2003).
The author thanks the following for expert discussions on the drugs reviewed: A. Coates (clinical antibiotic resistance and ARB concept); S. Shaunak (clinical antibiotic resistance, TLRs and innate immune system); N. Ktistakis (autophagy); D. Cavalla (drug repurposing); and members of the Science and Technology Advisory Committee of Antibiotics Research UK.
The author declares no competing financial interests.
About this article
Cite this article
Brown, D. Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?. Nat Rev Drug Discov 14, 821–832 (2015). https://doi.org/10.1038/nrd4675
Structural Modifications of the Quinolin-4-yloxy Core to Obtain New Staphylococcus aureus NorA Inhibitors
International Journal of Molecular Sciences (2020)
Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P. aeruginosa Biofilm Infections
Angewandte Chemie International Edition (2020)
Advanced Science (2020)
Specific localisation of ions in bacterial membranes unravels physical mechanism of effective bacteria killing by sanitiser
Scientific Reports (2020)
Journal of Enzyme Inhibition and Medicinal Chemistry (2020)