References:

1. Murray, C. J. et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 399, 629–655 (2022).
2. Laxminarayan, R. et al. Antibiotic resistance—the need for global solutions. Lancet Infect. Dis. 13, 1057–1098 (2013).
3. Adedeji, W. A. THE TREASURE CALLED ANTIBIOTICS. Ann. Ib. Postgrad. Med. 14, 56–57 (2016).
4. Kupferschmidt, K. Resistance fighters. Science 352, 758–761 (2016).
5. Lobanovska, M. & Pilla, G. Penicillin’s Discovery and Antibiotic Resistance: Lessons for the
Future? Yale J. Biol. Med. 90, 135–145 (2017).
6. Chung, H. et al. Rapid expansion and extinction of antibiotic resistance mutations during
treatment of acute bacterial respiratory infections. Nat. Commun. 13, 1231 (2022).
7. O’Dwyer, K. et al. Bacterial Resistance to Leucyl-tRNA Synthetase Inhibitor GSK2251052 Develops during Treatment of Complicated Urinary Tract Infections. Antimicrob. Agents
Chemother. 59, 289–298 (2015).
8. Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting
the challenges of antibacterial discovery. Nat. Rev. Drug Discov. 6, 29–40 (2007).
9. Reygaert, W. C. An overview of the antimicrobial resistance mechanisms of bacteria. AIMS
Microbiol. 4, 482–501 (2018).
10. Sun, D., Jeannot, K., Xiao, Y. & Knapp, C. W. Editorial: Horizontal Gene Transfer Mediated
Bacterial Antibiotic Resistance. Front. Microbiol. 10, (2019).
66
11. Courvalin, P. New plasmid-mediated resistances to antimicrobial agents. Arch. Microbiol. 189, 289–291 (2008).
12. Pribis, J. P. et al. Gamblers: an Antibiotic-induced Evolvable Cell Subpopulation Differentiated by Reactive-oxygen-induced General Stress Response. Mol. Cell 74, 785- 800.e7 (2019).
13. Kohanski, M. A., DePristo, M. A. & Collins, J. J. Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol. Cell 37, 311–320 (2010).
14. Børsting, C. & Morling, N. Single-Nucleotide Polymorphisms. in Encyclopedia of Forensic Sciences (Second Edition) (eds. Siegel, J. A., Saukko, P. J. & Houck, M. M.) 233–238 (Academic Press, 2013). doi:10.1016/B978-0-12-382165-2.00042-8.
15. Hunt, R., Sauna, Z. E., Ambudkar, S. V., Gottesman, M. M. & Kimchi-Sarfaty, C. Silent (Synonymous) SNPs: Should We Care About Them? in Single Nucleotide Polymorphisms: Methods and Protocols (ed. Komar, A. A.) 23–39 (Humana Press, 2009). doi:10.1007/978-1- 60327-411-1_2.
16. Ramanathan, B. et al. Next generation sequencing reveals the antibiotic resistant variants in the genome of Pseudomonas aeruginosa. PLoS ONE 12, e0182524 (2017).
17. Blair, J. M. A., Webber, M. A., Baylay, A. J., Ogbolu, D. O. & Piddock, L. J. V. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol. 13, 42–51 (2015).
18. Cochrane, S. A. et al. Antimicrobial lipopeptide tridecaptin A1 selectively binds to Gram- negative lipid II. Proc. Natl. Acad. Sci. U. S. A. 113, 11561–11566 (2016).
19. Cochrane, S. A. et al. Antimicrobial lipopeptide tridecaptin A1 selectively binds to Gram- negative lipid II. Proc. Natl. Acad. Sci. 113, 11561–11566 (2016).
67

20. Lee, M. & Sousa, M. C. Structural basis for substrate specificity in ArnB. A key enzyme in the polymyxin resistance pathway of Gram-negative bacteria. Biochemistry 53, 796–805 (2014).
21. Arroyo, L. A. et al. The pmrCAB Operon Mediates Polymyxin Resistance in Acinetobacter baumannii ATCC 17978 and Clinical Isolates through Phosphoethanolamine Modification of Lipid A. Antimicrob. Agents Chemother. 55, 3743–3751 (2011).
22. Gomes, C., Ruiz-Roldán, L., Mateu, J., Ochoa, T. J. & Ruiz, J. Azithromycin resistance levels and mechanisms in Escherichia coli. Sci. Rep. 9, 6089 (2019).
23. Heidary, M. et al. Mechanism of action, resistance, synergism, and clinical implications of azithromycin. J. Clin. Lab. Anal. 36, e24427 (2022).
24. Eliopoulos, G. M. & Huovinen, P. Resistance to Trimethoprim-Sulfamethoxazole. Clin. Infect. Dis. 32, 1608–1614 (2001).
25. Sanders, C. C. Ciprofloxacin: In Vitro Activity, Mechanism of Action, and Resistance. Rev. Infect. Dis. 10, 516–527 (1988).
26. Qin, T.-T. et al. SOS response and its regulation on the fluoroquinolone resistance. Ann. Transl. Med. 3, 358–358 (2015).
27. Grossman, T. H. Tetracycline Antibiotics and Resistance. Cold Spring Harb. Perspect. Med. 6, a025387 (2016).
28. Castro, R. A. D. et al. The Genetic Background Modulates the Evolution of Fluoroquinolone- Resistance in Mycobacterium tuberculosis. Mol. Biol. Evol. 37, 195–207 (2020).
29. Bui, T. & Preuss, C. V. Cephalosporins. in StatPearls (StatPearls Publishing, 2022).
68

30. Fischer, M. A. et al. Population structure-guided profiling of antibiotic resistance patterns in clinical Listeria monocytogenes isolates from Germany identifies pbpB3 alleles associated with low levels of cephalosporin resistance. Emerg. Microbes Infect. 9, 1804–1813.
31. Guinane, C. M., Cotter, P. D., Ross, R. P. & Hill, C. Contribution of Penicillin-Binding Protein Homologs to Antibiotic Resistance, Cell Morphology, and Virulence of Listeria monocytogenes EGDe. Antimicrob. Agents Chemother. 50, 2824–2828 (2006).
32. Breijyeh, Z., Jubeh, B. & Karaman, R. Resistance of Gram-Negative Bacteria to Current Antibacterial Agents and Approaches to Resolve It. Molecules 25, 1340 (2020).
33. Oliveira, J. & Reygaert, W. C. Gram Negative Bacteria. in StatPearls (StatPearls Publishing, 2022).
34. Choi, U. & Lee, C.-R. Distinct Roles of Outer Membrane Porins in Antibiotic Resistance and Membrane Integrity in Escherichia coli. Front. Microbiol. 10, 953 (2019).
35. Gottlieb, D. & Shaw, P. D. Antibiotics: Volume I Mechanism of Action. (Springer, 2013).
36. Rosas, N. C. & Lithgow, T. Targeting bacterial outer-membrane remodelling to impact
antimicrobial drug resistance. Trends Microbiol. 30, 544–552 (2022).
37. Zulauf, K. E. & Kirby, J. E. Discovery of small-molecule inhibitors of multidrug-resistance
plasmid maintenance using a high-throughput screening approach. Proc. Natl. Acad. Sci. U.
S. A. 117, 29839–29850 (2020).
38. Walkty, A. et al. Antimicrobial susceptibility of 2906 Pseudomonasaeruginosa clinical
isolates obtained from patients in Canadian hospitals over a period of 8 years: Results of the Canadian Ward surveillance study (CANWARD), 2008-2015. Diagn. Microbiol. Infect. Dis. 87, 60–63 (2017).
69

39. Zhanel, G. G. et al. 42936 Pathogens from Canadian hospitals: 10 years of results (2007-16) from the CANWARD surveillance study. J. Antimicrob. Chemother. 74, (2019).
40. Dewachter, L., Fauvart, M. & Michiels, J. Bacterial Heterogeneity and Antibiotic Survival: Understanding and Combatting Persistence and Heteroresistance. Mol. Cell 76, 255–267 (2019).
41. Gould, I. M. et al. New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance. Int. J. Antimicrob. Agents 39, 96–104 (2012).
42. Sholeh, M. et al. Antimicrobial resistance in Clostridioides (Clostridium) difficile derived from humans: a systematic review and meta-analysis. Antimicrob. Resist. Infect. Control 9, 158 (2020).
43. Allen, R. C. & Brown, S. P. Modified Antibiotic Adjuvant Ratios Can Slow and Steer the Evolution of Resistance: Co-amoxiclav as a Case Study. mBio 10, e01831-19 (2019).
44. Wright, G. D. Antibiotic Adjuvants: Rescuing Antibiotics from Resistance. Trends Microbiol. 24, 862–871 (2016).
45. Liu, Y., Li, R., Xiao, X. & Wang, Z. Antibiotic adjuvants: an alternative approach to overcome multi-drug resistant Gram-negative bacteria. Crit. Rev. Microbiol. 45, 301–314 (2019).
46. Bengtsson, T. et al. Plantaricin NC8 αβ exerts potent antimicrobial activity against Staphylococcus spp. and enhances the effects of antibiotics. Sci. Rep. 10, 3580 (2020).
47. Sjuts, H. et al. Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives. Proc. Natl. Acad. Sci. 113, 3509–3514 (2016).
70

48. Rogers, S. A., Huigens, R. W., Cavanagh, J. & Melander, C. Synergistic Effects between Conventional Antibiotics and 2-Aminoimidazole-Derived Antibiofilm Agents. Antimicrob. Agents Chemother. 54, 2112–2118 (2010).
49. Perry, J. A. et al. A macrophage-stimulating compound from a screen of microbial natural products. J. Antibiot. (Tokyo) 68, 40–46 (2015).
50. Audi, S. et al. The ‘top 100’ drugs and classes in England: an updated ‘starter formulary’ for trainee prescribers. Br. J. Clin. Pharmacol. 84, 2562–2571 (2018).
51. Oteo, J. et al. Increased Amoxicillin–Clavulanic Acid Resistance in Escherichia coli Blood Isolates, Spain. Emerg. Infect. Dis. 14, 1259–1262 (2008).
52. P, S. et al. Incidence and mechanisms of resistance to the combination of amoxicillin and clavulanic acid in Escherichia coli. Antimicrob. Agents Chemother. 39, (1995).
53. Lenski, R. E., Rose, M. R., Simpson, S. C. & Tadler, S. C. Long-Term Experimental Evolution in Escherichia coli. I. Adaptation and Divergence During 2,000 Generations. Am. Nat. 138, 1315–1341 (1991).
54. Toprak, E. et al. Building a morbidostat: an automated continuous-culture device for studying bacterial drug resistance under dynamically sustained drug inhibition. Nat. Protoc. 8, 555–567 (2013).
55. Baym, M. et al. Spatiotemporal microbial evolution on antibiotic landscapes. Science 353, 1147–1151 (2016).
56. Toprak, E. et al. Evolutionary paths to antibiotic resistance under dynamically sustained drug selection. Nat. Genet. 44, 101–105 (2011).
71

57. Spagnolo, F., Rinaldi, C., Sajorda, D. R. & Dykhuizen, D. E. Evolution of Resistance to Continuously Increasing Streptomycin Concentrations in Populations of Escherichia coli. Antimicrob. Agents Chemother. 60, 1336–1342 (2016).
58. Wadhams, G. H. & Armitage, J. P. Making sense of it all: bacterial chemotaxis. Nat. Rev. Mol. Cell Biol. 5, 1024–1037 (2004).
59. Ghaddar, N., Hashemidahaj, M. & Findlay, B. L. Access to high-impact mutations constrains the evolution of antibiotic resistance in soft agar. Sci. Rep. 8, 17023 (2018).
60. Bennett, P. M. Plasmid encoded antibiotic resistance: acquisition and transfer of antibiotic resistance genes in bacteria. Br. J. Pharmacol. 153, S347–S357 (2008).
61. Munita, J. M. & Arias, C. A. Mechanisms of Antibiotic Resistance. Microbiol. Spectr. 4, 4.2.15 (2016).
62. Szybalski, W. & Bryson, V. GENETIC STUDIES ON MICROBIAL CROSS RESISTANCE TO TOXIC AGENTS I. ,. J. Bacteriol. 64, 489–499 (1952).
63. Rathinakumar, R. & Wimley, W. C. High-throughput discovery of broad-spectrum peptide antibiotics. FASEB J. 24, 3232–3238 (2010).
64. Lewis, K. Platforms for antibiotic discovery. Nat. Rev. Drug Discov. 12, 371–387 (2013).
65. Hertzberg, R. P. & Pope, A. J. High-throughput screening: new technology for the 21st
century. Curr. Opin. Chem. Biol. 4, 445–451 (2000).
66. Taylor, P. L., Rossi, L., De Pascale, G. & Wright, G. D. A forward chemical screen identifies
antibiotic adjuvants in Escherichia coli. ACS Chem. Biol. 7, 1547–1555 (2012).
67. Broach, J. R. & Thorner, J. High-throughput screening for drug discovery. Nature 384, 14–16
(1996).
72

68. Carnero, A. High throughput screening in drug discovery. Clin. Transl. Oncol. 8, 482–490 (2006).
69. Wiegand, I., Hilpert, K. & Hancock, R. E. W. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat. Protoc. 3, 163– 175 (2008).
70. Kowalska-Krochmal, B. & Dudek-Wicher, R. The Minimum Inhibitory Concentration of Antibiotics: Methods, Interpretation, Clinical Relevance. Pathogens 10, 165 (2021).
71. Zhu, M., Tse, M. W., Weller, J., Chen, J. & Blainey, P. C. The future of antibiotics begins with discovering new combinations. Ann. N. Y. Acad. Sci. 1496, 82–96 (2021).
72. Tan, T. Y. et al. In Vitro Antibiotic Synergy in Extensively Drug-Resistant Acinetobacter baumannii: the Effect of Testing by Time-Kill, Checkerboard, and Etest Methods. Antimicrob. Agents Chemother. 55, 436–438 (2011).
73. Orhan, G., Bayram, A., Zer, Y. & Balci, I. Synergy Tests by E Test and Checkerboard Methods of Antimicrobial Combinations against Brucella melitensis. J. Clin. Microbiol. 43, 140–143 (2005).
74. Doern, C. D. When Does 2 Plus 2 Equal 5? A Review of Antimicrobial Synergy Testing. J. Clin. Microbiol. 52, 4124–4128 (2014).
75. Meletiadis, J., Pournaras, S., Roilides, E. & Walsh, T. J. Defining fractional inhibitory concentration index cutoffs for additive interactions based on self-drug additive combinations, Monte Carlo simulation analysis, and in vitro-in vivo correlation data for antifungal drug combinations against Aspergillus fumigatus. Antimicrob. Agents Chemother. 54, 602–609 (2010).
73

76. den Hollander, J. G., Mouton, J. W. & Verbrugh, H. A. Use of Pharmacodynamic Parameters To Predict Efficacy of Combination Therapy by Using Fractional Inhibitory Concentration Kinetics. Antimicrob. Agents Chemother. 42, 744–748 (1998).
77. Konaté, K. et al. Antibacterial activity against β- lactamase producing Methicillin and Ampicillin-resistants Staphylococcus aureus: fractional Inhibitory Concentration Index (FICI) determination. Ann. Clin. Microbiol. Antimicrob. 11, 18 (2012).
78. Li, R. C., Schentag, J. J. & Nix, D. E. The fractional maximal effect method: a new way to characterize the effect of antibiotic combinations and other nonlinear pharmacodynamic interactions. Antimicrob. Agents Chemother. 37, 523–531 (1993).
79. Prichard, M. N. & Shipman, C. A three-dimensional model to analyze drug-drug interactions. Antiviral Res. 14, 181–205 (1990).
80. Pandey, N. & Cascella, M. Beta Lactam Antibiotics. in StatPearls (StatPearls Publishing, 2022).
81. Krishnamurthy, M. et al. Enhancing the antibacterial activity of polymyxins using a nonantibiotic drug. Infect. Drug Resist. 12, 1393–1405 (2019).
82. Biswas, S., Brunel, J.-M., Dubus, J.-C., Reynaud-Gaubert, M. & Rolain, J.-M. Colistin: an update on the antibiotic of the 21st century. Expert Rev. Anti Infect. Ther. 10, 917–934 (2012).
83. Cannatelli, A. et al. In Vivo Emergence of Colistin Resistance in Klebsiella pneumoniae Producing KPC-Type Carbapenemases Mediated by Insertional Inactivation of the PhoQ/PhoP mgrB Regulator. Antimicrob. Agents Chemother. 57, 5521–5526 (2013).
74

84. Phan, M.-D. et al. Modifications in the pmrB gene are the primary mechanism for the development of chromosomally encoded resistance to polymyxins in uropathogenic Escherichia coli. J. Antimicrob. Chemother. 72, 2729–2736 (2017).
85. Berrocal-Lobo, M., Molina, A., Rodríguez-Palenzuela, P., García-Olmedo, F. & Rivas, L. Leishmania donovani: Thionins, plant antimicrobial peptides with leishmanicidal activity. Exp. Parasitol. 122, 247–249 (2009).
86. Zhang, L., Dhillon, P., Yan, H., Farmer, S. & Hancock, R. E. W. Interactions of Bacterial Cationic Peptide Antibiotics with Outer and Cytoplasmic Membranes of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44, 3317–3321 (2000).
87. Hancock, R. E. W. & Rozek, A. Role of membranes in the activities of antimicrobial cationic peptides. FEMS Microbiol. Lett. 206, 143–149 (2002).
88. Boix-Lemonche, G., Lekka, M. & Skerlavaj, B. A Rapid Fluorescence-Based Microplate Assay to Investigate the Interaction of Membrane Active Antimicrobial Peptides with Whole Gram-Positive Bacteria. Antibiotics 9, 92 (2020).
89. Aono, R., Ito, M. & Horikoshi, K. 1997. Measurement of cytoplasmic pH of the alkaliphile Bacillus lentus C-125 with a fluorescent pH probe. Microbiology 143, 2531–2536.
90. Molenaar, D., Abee, T. & Konings, W. N. Continuous measurement of the cytoplasmic pH in Lactococcus lactis with a fluorescent pH indicator. Biochim. Biophys. Acta BBA - Gen. Subj. 1115, 75–83 (1991).
91. Villanueva, J. A. et al. Salmonella enterica Infections Are Disrupted by Two Small Molecules That Accumulate within Phagosomes and Differentially Damage Bacterial Inner Membranes. mBio 13, e01790-22 (2022).
75

92. Stark, G. & Benz, R. The transport of potassium through lipid bilayer membranes by the neutral carriers valinomycin and monactin. J. Membr. Biol. 5, 133–153 (1971).
93. Liu, Y. et al. Drug repurposing for next-generation combination therapies against multidrug- resistant bacteria. Theranostics 11, 4910–4928 (2021).
94. Veale, C. G. L. Unpacking the Pathogen Box-An Open Source Tool for Fighting Neglected Tropical Disease. ChemMedChem 14, 386–453 (2019).
95. About the Pathogen Box | Medicines for Malaria Venture. https://www.mmv.org/mmv- open/pathogen-box/about-pathogen-box.
96. Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299–304 (2017).
97. Prajapati, J. D., Kleinekathöfer, U. & Winterhalter, M. How to Enter a Bacterium: Bacterial Porins and the Permeation of Antibiotics. Chem. Rev. 121, 5158–5192 (2021).
98. Schulz, G. E. Bacterial porins: structure and function. Curr. Opin. Cell Biol. 5, 701–707 (1993).
99. Markus, A. C. & Spencer, A. G. Treatment of Chronic Lead-poisoning with Calcium Disodium Versenate. Br. Med. J. 2, 883–885 (1955).
100. Clarke, N. E., Clarke, C. N. & Mosher, R. E. The in vivo dissolution of metastatic calcium; an approach to atherosclerosis. Am. J. Med. Sci. 229, 142–149 (1955).
101. Clarke, C. N., Clarke, N. E. & Mosher, R. E. Treatment of angina pectoris with disodium ethylene diamine tetraacetic acid. Am. J. Med. Sci. 232, 654–666 (1956).
76

102. Chaudhary, M. & Payasi, A. Clinical, microbial efficacy and tolerability of Elores, a novel antibiotic adjuvant entity in ESBL producing pathogens: Prospective randomized controlled clinical trial. J. Pharm. Res. 7, 275–280 (2013).
103. Goldschmidt, M. C. & Wyss, O. The role of tris in EDTA toxicity and lysozyme lysis. J. Gen. Microbiol. 47, 421–431 (1967).
104. Nikaido, H. Molecular Basis of Bacterial Outer Membrane Permeability Revisited. Microbiol. Mol. Biol. Rev. 67, 593–656 (2003).
105. Pelletier, C., Bourlioux, P. & van Heijenoort, J. Effects of sub-minimal inhibitory concentrations of EDTA on growth of Escherichia coli and the release of lipopolysaccharide. FEMS Microbiol. Lett. 117, 203–206 (1994).
106. Umerska, A. et al. Synergistic Effect of Combinations Containing EDTA and the Antimicrobial Peptide AA230, an Arenicin-3 Derivative, on Gram-Negative Bacteria. Biomolecules 8, (2018).
107. Salmonella Homepage | CDC. https://www.cdc.gov/salmonella/index.html (2022).
108. Takemura, R. & Werb, Z. Secretory products of macrophages and their physiological
functions. Am. J. Physiol. 246, C1-9 (1984).
109. Höner Zu Bentrup, K., Miczak, A., Swenson, D. L. & Russell, D. G. Characterization of
activity and expression of isocitrate lyase in Mycobacterium avium and Mycobacterium
tuberculosis. J. Bacteriol. 181, 7161–7167 (1999).
110. Kornberg, H. L. The role and control of the glyoxylate cycle in Escherichia coli. Biochem.
J. 99, 1–11 (1966).
77

111. Hammerer, F., Chang, J. H., Duncan, D., Castañeda Ruiz, A. & Auclair, K. Small Molecule Restores Itaconate Sensitivity in Salmonella enterica: A Potential New Approach to Treating Bacterial Infections. Chembiochem Eur. J. Chem. Biol. 17, 1513–1517 (2016).
112. Strelko, C. L. et al. Itaconic acid is a mammalian metabolite induced during macrophage activation. J. Am. Chem. Soc. 133, 16386–16389 (2011).
113. Levy, S. E. & Myers, R. M. Advancements in Next-Generation Sequencing. Annu. Rev. Genomics Hum. Genet. 17, 95–115 (2016).
114. Salipante, S. J. et al. Performance Comparison of Illumina and Ion Torrent Next- Generation Sequencing Platforms for 16S rRNA-Based Bacterial Community Profiling. Appl. Environ. Microbiol. 80, 7583–7591 (2014).
115. Quail, M. A. et al. A large genome center’s improvements to the Illumina sequencing system. Nat. Methods 5, 1005–1010 (2008).
116. Sequencing-by-Synthesis: Explaining the Illumina Sequencing Technology. https://bitesizebio.com/13546/sequencing-by-synthesis-explaining-the-illumina- sequencing-technology/ (2012).
117. Bankevich, A. et al. SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. J. Comput. Biol. J. Comput. Mol. Cell Biol. 19, 455–477 (2012). 118. Gurevich, A., Saveliev, V., Vyahhi, N. & Tesler, G. QUAST: quality assessment tool for
genome assemblies. Bioinforma. Oxf. Engl. 29, 1072–1075 (2013).
119. Seemann, T. Snippy. (2022).
120. Backman, T. W. H., Cao, Y. & Girke, T. ChemMine tools: an online service for analyzing
and clustering small molecules. Nucleic Acids Res. 39, W486-491 (2011).
78

121. Shirai, K. & Matsuoka, M. Structure and properties of hematein derivatives. Dyes Pigments 32, 159–169 (1996).
122. HUNG, M.-S. et al. Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model. Int. J. Oncol. 43, 1517–1522 (2013).
123. Xu, H.-X. & Lee, S. F. The antibacterial principle of Caesalpina sappan. Phytother. Res. PTR 18, 647–651 (2004).
124. Amin, M. U., Khurram, M., Khattak, B. & Khan, J. Antibiotic additive and synergistic action of rutin, morin and quercetin against methicillin resistant Staphylococcus aureus. BMC Complement. Altern. Med. 15, 59 (2015).
125. Arima, H., Ashida, H. & Danno, G. Rutin-enhanced antibacterial activities of flavonoids against Bacillus cereus and Salmonella enteritidis. Biosci. Biotechnol. Biochem. 66, 1009– 1014 (2002).
126. Peng, L.-Y. et al. Rutin inhibits quorum sensing, biofilm formation and virulence genes in avian pathogenic Escherichia coli. Microb. Pathog. 119, 54–59 (2018).
127. Wu, T. et al. A structure–activity relationship study of flavonoids as inhibitors of E. coli by membrane interaction effect. Biochim. Biophys. Acta BBA - Biomembr. 1828, 2751–2756 (2013).
128. Saidkhodzhaev, A. I. & Malikov, V. M. Structure of ugaferin and some properties of ugamdiol derivatives. Chem. Nat. Compd. 14, 614–616 (1978).
129. Hall, M. J., Middleton, R. F. & Westmacott, D. The fractional inhibitory concentration (FIC) index as a measure of synergy. J. Antimicrob. Chemother. 11, 427–433 (1983).
79

130. Tsubery, H., Ofek, I., Cohen, S. & Fridkin, M. Structure-function studies of polymyxin B nonapeptide: implications to sensitization of gram-negative bacteria. J. Med. Chem. 43, 3085–3092 (2000).
131. H, T., I, O., S, C. & M, F. Structure-function studies of polymyxin B nonapeptide: implications to sensitization of gram-negative bacteria. J. Med. Chem. 43, (2000).
132. Bessonova, I. A. Acetylhaplophyllidine, a new alkaloid fromHaplophyllum perforatum. Chem. Nat. Compd. 35, 589–590 (1999).
133. da Silva, H. C. et al. Structural characterization, antibacterial activity and NorA efflux pump inhibition of flavonoid fisetinidol. South Afr. J. Bot. 132, 140–145 (2020).
134. Boualia, I. et al. Synthesis of novel 3-(quinazol-2-yl)-quinolines via SNAr and aluminum chloride-induced (hetero) arylation reactions and biological evaluation as proteasome inhibitors. Tetrahedron Lett. 61, 151805 (2020).
135. Zhang, B., Liu, Z., Xia, S., Liu, Q. & Gou, S. Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors. Eur. J. Med. Chem. 216, 113300 (2021).
136. Hubbard, A. T. M. et al. Mechanism of Action of a Membrane-Active Quinoline-Based Antimicrobial on Natural and Model Bacterial Membranes. Biochemistry 56, 1163–1174 (2017).
137. Insuasty, D. et al. Antimicrobial Activity of Quinoline-Based Hydroxyimidazolium Hybrids. Antibiotics 8, 239 (2019).
138. Sohel, A. J., Shutter, M. C. & Molla, M. Fluoxetine. in StatPearls (StatPearls Publishing, 2022).
80

139. Melnyk, A. H., Wong, A. & Kassen, R. The fitness costs of antibiotic resistance mutations. Evol. Appl. 8, 273–283 (2015).
140. Song, M. et al. A broad-spectrum antibiotic adjuvant reverses multidrug-resistant Gram- negative pathogens. Nat. Microbiol. 5, 1040–1050 (2020).
141. Plackett, B. Why big pharma has abandoned antibiotics. Nature 586, S50–S52 (2020).
142. qiworks. Pipeline. Bugworks https://bugworksresearch.com/pipeline/ (2021).
143. MacVane, S. H. Antimicrobial Resistance in the Intensive Care Unit: A Focus on Gram-
Negative Bacterial Infections. J. Intensive Care Med. 32, 25–37 (2017).
144. Spalenka, J. et al. Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen
Box. Antimicrob. Agents Chemother. 62, e01640-17 (2018).
145. Jeong, J. et al. Pathogen Box screening for hit identification against Mycobacterium
abscessus. PLOS ONE 13, e0195595 (2018).
146. Vila, T. & Lopez-Ribot, J. L. Screening the Pathogen Box for Identification of Candida
albicans Biofilm Inhibitors. Antimicrob. Agents Chemother. 61, e02006-16 (2016).
147. Sahoo, B. M. et al. Drug Repurposing Strategy (DRS): Emerging Approach to Identify
Potential Therapeutics for Treatment of Novel Coronavirus Infection. Front. Mol. Biosci. 8,
(2021).
148. Kim, J. H. & Scialli, A. R. Thalidomide: the tragedy of birth defects and the effective
treatment of disease. Toxicol. Sci. Off. J. Soc. Toxicol. 122, 1–6 (2011).
149. Vargesson, N. Thalidomide‐induced teratogenesis: History and mechanisms. Birth
Defects Res. 105, 140–156 (2015).
81

150. Rehman, W., Arfons, L. M. & Lazarus, H. M. The Rise, Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development. Ther. Adv. Hematol. 2, 291–308 (2011).
151. Schein, C. H. Repurposing approved drugs on the pathway to novel therapies. Med. Res. Rev. 40, 586–605 (2020).
152. Andersson, D. I., Nicoloff, H. & Hjort, K. Mechanisms and clinical relevance of bacterial heteroresistance. Nat. Rev. Microbiol. 17, 479–496 (2019).
153. Nicoloff, H., Hjort, K., Levin, B. R. & Andersson, D. I. The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification. Nat. Microbiol. 4, 504–514 (2019).
154. Wang, Y. et al. Heteroresistance Is Associated With in vitro Regrowth During Colistin Treatment in Carbapenem-Resistant Klebsiella pneumoniae. Front. Microbiol. 13, (2022).
155. Ezadi, F., Ardebili, A. & Mirnejad, R. Antimicrobial Susceptibility Testing for Polymyxins: Challenges, Issues, and Recommendations. J. Clin. Microbiol. 57, e01390-18 (2019).
156. Kim, J. W. & Lee, K. J. Single-nucleotide polymorphisms in a vancomycin-resistant Staphylococcus aureus strain based on whole-genome sequencing. Arch. Microbiol. 202, 2255–2261 (2020).
157. Lamers, R. P., Cavallari, J. F. & Burrows, L. L. The efflux inhibitor phenylalanine-arginine beta-naphthylamide (PAβN) permeabilizes the outer membrane of gram-negative bacteria. PloS One 8, e60666 (2013).