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• W2401496781 abstract "Future Medicinal ChemistryVol. 8, No. 9 EditorialFree AccessOvercoming β-lactam resistance in Gram-negative pathogensKaren BushKaren Bush*Author for correspondence: E-mail Address: karbush@indiana.edu Indiana University, 212 S. Hawthorne Dr., Bloomington, IN 47405, USASearch for more papers by this authorPublished Online:26 May 2016https://doi.org/10.4155/fmc-2016-0076AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: aminoglycosidesβ-lactamβ-lactamaseβ-lactamase inhibitortetracyclinesFirst draft submitted: 8 April 2016; Accepted for publication: 11 April 2016; Published online: 26 May 2016Resistance has been driving the development of new antibiotics ever since penicillin-resistant staphylococci began to be reported in the mid-1940s. Although early antibiotics were targeted primarily against the Gram-positive cocci, their use soon selected for β-lactam-resistant Gram-negative bacteria. Due to the threats posed by a growing diversity of β-lactam-hydrolyzing β-lactamases in the enteric bacteria, antibiotic development programs placed greater emphasis on the identification of naturally occurring non-β-lactam antibiotics such as aminoglycosides and tetracyclines, followed by optimization of (fluoro)quinolone molecules as a means of circumventing β-lactam resistance in Gram-negative bacteria [1]. In spite of these efforts, more potent β-lactams continued to replenish the antibiotic armamentarium, serving to drive selection of broader spectrum β-lactamases which appeared on mobile genetic elements in most Gram-negative bacteria. Unfortunately, many of these newer enzymes appeared on transposons or plasmids that carried additional resistance determinants, thereby resulting in multidrug-resistant Gram-negative pathogens that could be selected by one of a number of antibiotics [2].Within the decade spanning the beginning of the 21st century, susceptibility to some of the most reliable antibacterial agents eroded significantly. In surveillance studies reported in 2001, low resistance rates (2.4–5.8%) were reported for levofloxacin and gentamicin in large collections of sequentially collected clinical isolates of Escherichia coli and Klebsiella pneumoniae from the USA. Resistance to expanded-spectrum cephalosporins, piperacillin-tazobactam and imipenem in these isolates was also low, with no carbapenem resistance reported, and resistance to the cephalosporins peaking at 6.8% in K. pneumoniae [3,4]. However, this situation changed dramatically in a short period of time. Isolates collected from US pneumonia patients in 2012 demonstrated elevated resistance rates for all the drugs tested; in K. pneumoniae isolates levofloxacin and gentamicin resistance was 21–24%, and for the β-lactams, resistance increased to 31% for ceftazidime and 8.9% for meropenem, while in E. coli levofloxacin resistance was 34% [5]. In a set of Polish hospitals, carbapenem resistance in the Enterobacteriaceae isolates rose to 17% by 2013 [6]; resistance to the expanded-spectrum cephalosporins was reported to be 47% among Enterobacteriaceae isolates from Shanghai nursing home residents [7]. This increase in β-lactam resistance is due largely to the exponential increase in β-lactamases that collectively are capable of inactivating all β-lactams [1].Most disconcerting among the β-lactamases are the carbapenem-hydrolyzing enzymes, the carbapenemases that emerged on plasmids in the early 1990s and that have now proliferated over the globe. These enzymes hold the ability to hydrolyze virtually every β-lactam-containing molecule [2]. They belong to two different molecular classes depending on their hydrolysis mechanisms: those that utilize serine at their active site and those that contain at least one zinc ion to facilitate hydrolysis. The latter, named metallo-β-lactamases, or MBLs, include the NDM-1 MBL that recently emerged from India [8] and that has rapidly spread worldwide in multidrug-resistant Gram-negative pathogens [9]. Almost without exception the carbapenemases exist in concert with at least one other β-lactamase, and usually with additional resistance determinants [2]. As a result, carbapenem-resistant Enterobacteriaceae are being reported as 91% resistant to levofloxacin, 63% resistant to amikacin and, most unsettling, 26% resistant to colistin [6].Drugs of last resort in the last decade for the treatment of multidrug-resistant Gram-negative bacteria became colistin and tigecycline, with 99–100% susceptibility recorded for enteric bacteria in the 2012 study of pneumonia isolates; 1.5% colistin resistance was recorded for Pseudomonas aeruginosa and up to 8% resistance in Acinetobacter isolates [5]. Resistance to both these agents, however, continues to increase, with multiple resistance mechanisms described for both agents [10]. Perhaps the most disturbing development within the past year has been the identification of colistin-resistant isolates carrying the plasmid-encoded mcr-1 gene that encodes a phosphoethanolamine transferase, the first plasmid-borne resistance determinant for polymyxins [11]. The gene, first described in food animals from China, and now reported from multiple animal and human sources throughout the world, is frequently identified in isolates that are β-lactam resistant, with co-transfer of both mcr-1 and β-lactamase genes. Although co-resistance has been reported to have been acquired during therapy with cephalosporins [12], the origin of the mcr-1 gene likely has arisen through environmental transfer. The question then arises as to what is available to treat infections caused by these highly resistant bacteria.Historically, one approach to the treatment of β-lactam-resistant infections was to introduce β-lactamase inhibitors in combination with broad-spectrum penicillins. Since 2014, two new β-lactamase inhibitor combinations have been approved for clinical use in the USA with indications that include the treatment of infections caused by Gram-negative bacteria [13]. The introduction of ceftolozane-tazobactam has provided a potent combination for treatment of infections caused by P. aeruginosa [13] with less than 6% resistance reported in recent USA and European pseudomonal isolates [5]. Susceptibility to the combination in enteric bacteria, however, is lower due to the lability of ceftolozane to hydrolysis by extended-spectrum β-lactamases (ESBLs) in K. pneumoniae [5]. Although ceftolozane resistance due to mutations in the chromosomal AmpC β-lactamase from P. aeruginosa has recently been described [14], this resistance is less common. The ceftazidime-avibactam cephalosporin-β-lactamase inhibitor combination was approved in 2015 after only Phase II data had been compiled. This combination includes avibactam, a novel diazabicyclo[3.2.1]octanone (DBO) non-β-lactam β-lactamase inhibitor that has been used as a model platform by a number of medicinal chemistry groups in attempts to improve upon the cephalosporin-avibactam inhibitor combination [13]. Avibactam, and its most notable followers relebactam and OP0595, represent major improvements over earlier β-lactamase inhibitors that were only effective against narrow spectrum β-lactamases. The DBOs include those same enzymes in their inhibitory spectrum, but have additional potent inhibitory activity against the serine carbapenemases and the AmpC cephalosporinases [13]. They are being developed with cephalosporins, monobactams and carbapenems in order to obtain the broadest spectrum of activity to cover resistant Gram-negative pathogens. The advantage of the avibactam–monobactam combination is the observed stability of aztreonam to hydrolysis by MBLs, providing a β-lactam-related option to counteracting resistance in MBL-producing Gram-negative bacteria [13]. In addition to the DBOs in development, vaborbactam represents a novel approach to β-lactamase inhibition by using a unique cyclic boronic acid template to inhibit serine β-lactamases, especially targeting serine carbapenemases [13]. For the carbapenem-inhibitor combinations such as the relebactam–imipenem and vaborbactam–meropenem combinations, development times may be extended, as enrollment in clinical trials to demonstrate efficacy against resistant pathogens is often slow [15], especially when the absolute number of carbapenem-resistant pathogens may be quite low at many recruitment sites.Novel β-lactams in development include the monobactam BAL30072 and the cephalosporin S-649266, both of which are siderophore-containing β-lactam molecules [13]. Historically, β-lactams decorated with various siderophores have not been successful in advancing into therapeutic clinical trials. The antibiotic literature over the past 30 years has multiple examples of penicillins, cephalosporins, carbapenems and monobactams designed with siderophore structures to allow utilization of iron transport systems as a means of facilitating entry into Gram-negative bacteria [16]. Many of these molecules failed to advance due to the rapid selection of resistance in various genes involved with iron transport. However, both BAL30072 and S-649266 have demonstrated reduced selection frequencies compared with earlier studies [13]. In addition, S-649266 has demonstrated stability to a variety of β-lactamases, with an expanded spectrum of activity against carbapenem-resistant Enterobacteriaceae including a number of strains producing MBLs [17]. It will be interesting to follow the development of this novel cephalosporin through therapeutic clinical trials to determine whether its attractive in vitro profile can be maintained during the course of human infections.Other promising agents active against multidrug-resistant Gram-negative bacteria include the novel aminoglycoside plazomicin, and the tetracyclines eravacycline and omadacycline. Plazomicin and eravacycline have demonstrated potentially useful antibacterial activity against carbapenem-producing Enterobacteriaceae and Acinetobacter spp. [18,19]. They represent the possibility of using drugs outside the β-lactam area, a requirement for patients who may not be able to tolerate β-lactam therapy. However, resistance issues have been identified for each drug, with eravacycline sharing common resistance mechanisms with tigecycline, and plazomicin being vulnerable to resistance caused by rRNA methyltransferases that are often transferred on the same plasmid(s) as the NDM-1 (MBL)-encoding gene [20]. Because of the past success of the polymyxins, other antimicrobial peptides or peptide mimetics could be of interest. Although many of these molecules have encountered issues in their development as a therapeutic agent, brilacidin with its broad-spectrum antibacterial activity is perhaps one of the most promising of the current investigational agents in this class [21].As noted above, a number of antibacterial agents with activity against many β-lactam-resistant Gram-negative pathogens have recently been approved or are in late-stage development. This is good. However, the downside is that these molecules are all closely related to drug classes that have been used extensively in the past. This is not necessarily bad. Although there have been many suggestions that ‘newer is better’, the older drugs have served the infectious disease community well, and are still somewhat effective. Susceptibility rates for amikacin and carbapenems in large populations of European Enterobacteriaceae are still >95% [6]. However, it is the 5% resistant population that demands attention. Resistance is being transferred not only within the nosocomial setting, or from long-term care facilities, but also from person to person through international travel that allows dissemination of the worst of the resistance determinants. Resistance genes in food animals in the Asia-Pacific region may be transferred in meat that is sold in North America. Resistance is global and will not diminish unless major containment efforts are made on a global scale. For the future, new drugs will continue to be needed. Combination therapy will need to be considered, not just for β-lactams but across drug classes. Treatment of infections caused by non-fermentative bacteria in particular may routinely need to be treated with drug combinations, perhaps an aminoglycoside plus a β-lactam, in order to counteract colistin-resistant organisms [19]. Finally, antibacterial drug discovery and development must continue to identify novel therapeutic approaches, as well as novel compounds, in our efforts to try to manage these highly resistant Gram-negative pathogens.Financial & competing interests disclosureThe author receives retirement compensation from Bristol-Myers Squibb, Johnson & Johnson and Pfizer (Wyeth). The author is the past or present consultant or serves on a Scientific Advisory Board for Achaogen, Allecra, Cempra, Cubist, Entasis, Gladius, Melinta, Merck, Naeja, Rempex, Roche, Shionogi, The Medicines Company, Tetraphase and Warp Drive. The author is also a shareholder of Johnson & Johnson. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.References1 Bush K, Craig WA, Dalie J et al. American Society for Microbiology 50 Years of ICAAC: 1961–2010. Contributions to Science. Washington, DC, USA (2010).Google Scholar2 Bush K. Carbapenemases: partners in crime. J. Global Antimicrob. Resist. 1(1), 7–16 (2013).Crossref, Medline, Google Scholar3 Mathai D, Jones RN, Pfaller MA, America SPGN. Epidemiology and frequency of resistance among pathogens causing urinary tract infections in 1,510 hospitalized patients: a report from the SENTRY Antimicrobial Surveillance Program (North America). Diagn. Microbiol. Infect. Dis. 40(3), 129–136 (2001).Crossref, Medline, CAS, Google Scholar4 Sahm DF, Critchley IA, Kelly LJ et al. Evaluation of current activities of fluoroquinolones against Gram-negative bacilli using centralized in vitro testing and electronic surveillance. Antimicrob. Agents Chemother. 45(1), 267–274 (2001).Crossref, Medline, CAS, Google Scholar5 Farrell DJ, Sader HS, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012). Int. J. Antimicrob. Agents 43(6), 533–539 (2014).Crossref, Medline, CAS, Google Scholar6 Sader HS, Castanheira M, Flamm RK, Mendes RE, Farrell DJ, Jones RN. Tigecycline activity tested against carbapenem-resistant Enterobacteriaceae from 18 European nations: results from the SENTRY surveillance program (2010–2013). Diagn. Microbiol. Infect. Dis. 83(2), 183–186 (2015).Crossref, Medline, CAS, Google Scholar7 Zhao SY, Zhang J, Zhang YL et al. Epidemiology and risk factors for faecal extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) carriage derived from residents of seven nursing homes in western Shanghai, China. Epidemiol. Infect. 144(4), 695–702 (2016).Crossref, Medline, CAS, Google Scholar8 Yong D, Toleman MA, Giske CG et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob. Agents Chemother. 53(12), 5046–5054 (2009).Crossref, Medline, CAS, Google Scholar9 Biedenbach D, Bouchillon S, Hackel M et al. Dissemination of NDM metallo-β-lactamase genes among clinical isolates of Enterobacteriaceae collected during the SMART global surveillance study from 2008 to 2012. Antimicrob. Agents Chemother. 59, 826–830 (2015).Crossref, Medline, CAS, Google Scholar10 Veleba M, Schneiders T. Tigecycline resistance can occur independently of the ramA gene in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 56(8), 4466–4467 (2012).Crossref, Medline, CAS, Google Scholar11 Liu YY, Wang Y, Walsh TR et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect. Dis. 16(2), 161–168 (2016).Crossref, Medline, CAS, Google Scholar12 Jayol A, Nordmann P, Desroches M, Decousser J-W, Poirel L. Acquisition of broad-spectrum cephalosporin resistance leading to colistin resistance in Klebsiella pneumoniae. Antimicrob. Agents Chemother. 60(5), 3199–3201 (2016).Crossref, Medline, CAS, Google Scholar13 Bush K. Investigational agents for the treatment of Gram-negative bacterial infections: a reality check. ACS Infect. Dis. 1(11), 509–511 (2015).Crossref, Medline, CAS, Google Scholar14 Berrazeg M, Jeannot K, Enguéné VYN et al. Mutations in ß-lactamase AmpC increase resistance of Pseudomonas aeruginosa isolates to antipseudomonal cephalosporins. Antimicrob. Agents Chemother. 59(10), 6248–6255 (2015).Crossref, Medline, CAS, Google Scholar15 Tomayko JF, Rex JH, Tenero DM, Goldberger M, Eisenstein BI. The challenge of antimicrobial resistance: new regulatory tools to support product development. Clin. Pharmacol. Therapeut. 96(2), 166–168 (2014).Crossref, Medline, CAS, Google Scholar16 Budzikiewicz H. Siderophore–antibiotic conjugates used as trojan horses against Pseudomonas aeruginosa. Curr. Topics Med. Chem. 1(1), 73–82 (2001).Crossref, Medline, CAS, Google Scholar17 Kohira N, West J, Ito A et al. In vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains. Antimicrob. Agents Chemother. 60(2), 729–734 (2016).Crossref, Medline, CAS, Google Scholar18 Abdallah M, Olafisoye O, Cortes C, Urban C, Landman D, Quale J. Activity of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including multidrug-resistant isolates, from New York City. Antimicrob. Agents Chemother. 59(3), 1802–1805 (2015).Crossref, Medline, Google Scholar19 Garcia-Salguero C, Rodriguez-Avial I, Picazo JJ, Culebras E. Can plazomicin alone or in combination be a therapeutic option against carbapenem-resistant Acinetobacter baumannii? Antimicrob. Agents Chemother. 59(10), 5959–5966 (2015).Crossref, Medline, CAS, Google Scholar20 Livermore DM, Mushtaq S, Warner M et al. Activity of aminoglycosides, including ACHN-490, against carbapenem-resistant Enterobacteriaceae isolates. J. Antimicrob. Chemother. 66(1), 48–53 (2011).Crossref, Medline, CAS, Google Scholar21 Mensa B, Howell GL, Scott R, Degrado WF. Comparative mechanistic studies of brilacidin, daptomycin, and the antimicrobial peptide LL16. Antimicrob. Agents Chemother. 58(9), 5136–5145 (2014).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByDevelopment of Peptide-based Metallo-β-lactamase Inhibitors as a New Strategy to Combat Antimicrobial Resistance: A Mini-reviewCurrent Pharmaceutical Design, Vol. 28, No. 44Synthesis of C2 ‐Formamide(thiophene)pyrazolyl‐ C4 ’‐carbaldehyde and their Transformation to Schiff's Bases and Stereoselective trans ‐β‐Lactams: Mechanistic and Theoretical Insights4 October 2022 | ChemistrySelect, Vol. 7, No. 37Kinugasa Reaction for DNA-Encoded β-Lactam Library Synthesis2 August 2022 | Organic Letters, Vol. 24, No. 31Live-Cell Profiling of Penicillin-Binding Protein Inhibitors in Escherichia coli MG165528 June 2022 | ACS Infectious Diseases, Vol. 8, No. 7Overcoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-125 June 2021 | FEMS Microbiology Letters, Vol. 368, No. 11Profile of Enterobacteria Resistant to Beta-Lactams15 July 2020 | Antibiotics, Vol. 9, No. 7Synthesis and Penicillin‐binding Protein Inhibitory Assessment of Dipeptidic 4‐Phenyl‐β‐lactams from α‐Amino Acid‐derived Imines28 November 2019 | Chemistry – An Asian Journal, Vol. 15, No. 1IS26-Mediated Transfer of blaNDM–1 as the Main Route of Resistance Transmission During a Polyclonal, Multispecies Outbreak in a German Hospital17 December 2019 | Frontiers in Microbiology, Vol. 10α‐Unsaturated 3‐Amino‐1‐carboxymethyl‐β‐lactams as Bacterial PBP Inhibitors: Synthesis and Biochemical Assessment19 November 2019 | Chemistry – A European Journal, Vol. 25, No. 70Comparison of Antibiotic Resistance Mechanisms in Antibiotic-Producing and Pathogenic Bacteria21 September 2019 | Molecules, Vol. 24, No. 19In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB12 February 2018 | Chemical Biology & Drug Design, Vol. 91, No. 6Antibacterial and β-Lactamase Inhibitory Activity of Monocyclic β-Lactams16 August 2017 | Medicinal Research Reviews, Vol. 38, No. 2Clonal relationships, antimicrobial susceptibilities, and molecular characterization of extended-spectrum beta-lactamase-producing Escherichia coli isolates from urinary tract infections and fecal samples in Southeast Iran1 February 2018 | Revista da Sociedade Brasileira de Medicina Tropical, Vol. 51, No. 1A review on cell wall synthesis inhibitors with an emphasis on glycopeptide antibiotics1 January 2017 | MedChemComm, Vol. 8, No. 3Part I: new frontiers in antibacterial drug discoveryMark G Moloney21 June 2016 | Future Medicinal Chemistry, Vol. 8, No. 9 Vol. 8, No. 9 Follow us on social media for the latest updates Metrics History Published online 26 May 2016 Published in print June 2016 Information© Future Science LtdKeywordsaminoglycosidesβ-lactamβ-lactamaseβ-lactamase inhibitortetracyclinesFinancial & competing interests disclosureThe author receives retirement compensation from Bristol-Myers Squibb, Johnson & Johnson and Pfizer (Wyeth). The author is the past or present consultant or serves on a Scientific Advisory Board for Achaogen, Allecra, Cempra, Cubist, Entasis, Gladius, Melinta, Merck, Naeja, Rempex, Roche, Shionogi, The Medicines Company, Tetraphase and Warp Drive. The author is also a shareholder of Johnson & Johnson. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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