Present and future etiological treatment of bacterial pneumonia 3. The antibacterial drugs under development

A.A. Abaturov, T.A. Kryuchko


The rapid spread of antibiotic-resistant bacterial strains necessitates the development of new antibacterial agents and a review of the guidelines for etiological treatment of bacterial infections, including pneumonia. Currently, new antibacterial agents are being developed that disrupt the biosynthesis of peptidoglycan, teichoic and lipoteichoic acids, and also block the attachment of virulent factors to the bacterial wall. New molecules of old classes of antibiotics and representatives of new classes of antibiotics with their targets (lipid II and III, teichoic and lipoteichoic acids, alanine racemase, and sortase A) will become practical tools in clinical practice in the very near future. The goals and mechanisms of action of new antibacterial compounds predetermine their clinical prospects in future strategies for the treatment of infectious bacterial diseases.


bacterial pneumonia; children; antibacterial drugs


Atkinson DJ, Naysmith BJ, Furkert DP, Brimble M.A. Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis. Beilstein J Org Chem. 2016 Nov 7;12:2325-42. doi: 10.3762/bjoc.12.226.

Azam MA, Jayaram U. Inhibitors of alanine racemase enzyme: a review. J Enzyme Inhib Med Chem. 2016 Aug;31(4):517-26. doi: 10.3109/14756366.2015.1050010.

Bae J, Jeon JE, Lee YJ, et al. Sesterterpenes from the tropical sponge Coscinoderma sp. J Nat Prod. 2011 Aug 26;74(8):1805-11. doi: 10.1021/np200492k.

Biedenbach DJ, Jones RN. Multicenter evaluation of the in vitro activity of dalbavancin tested against staphylococci and streptococci in 5 European countries: results from the DECIDE Surveillance Program (2007). Diagn Microbiol Infect Dis. 2009 Jun;64(2):177-84. doi: 10.1016/j.diagmicrobio.2008.12.019.

Brade KD, Rybak JM, Rybak MJ. Oritavancin: A New Lipoglycopeptide Antibiotic in the Treatment of Gram-Positive Infections. Infect Dis Ther. 2016 Mar;5(1):1-15. doi: 10.1007/s40121-016-0103-4.

Bradshaw WJ, Davies AH, Chambers CJ, et al. Molecular features of the sortase enzyme family. FEBS J. 2015 Jun;282(11):2097-114. doi: 10.1111/febs.13288.

Cascioferro S, Totsika M, Schillaci D. Sortase A: an ideal target for anti-virulence drug development. Microb Pathog. 2014 Dec;77:105-12. doi: 10.1016/j.micpath.2014.10.007.

Chan AH, Yi SW, Weiner EM, et al. NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors. Chem Biol Drug Des. 2017 Feb;90(3):327-44. doi: 10.1111/cbdd.12962.

Chuan J, Zhang Y, He X, et al. Systematic Review and Meta-Analysis of the Efficacy and Safety of Telavancin for Treatment of Infectious Disease: Are We Clearer? Front Pharmacol. 2016 Sep 23;7:330. doi: 10.3389/fphar.2016.00330.

Clancy KW, Melvin JA, McCafferty DG. Sortase transpeptidases: insights into mechanism, substrate specificity, and inhibition. Biopolymers. 2010;94(4):385-96. doi: 10.1002/bip.21472.

Corey GR, Rubinstein E, Stryjewski ME, et al. Potential role for telavancin in bacteremic infections due to gram-positive pathogens: focus on Staphylococcus aureus. Clin Infect Dis. 2015 Mar 1;60(5):787-96. doi: 10.1093/cid/ciu971.

Crotty MP, Krekel T, Burnham CA, Ritchie DJ. New Gram-Positive Agents: the Next Generation of Oxazolidinones and Lipoglycopeptides. J Clin Microbiol. 2016 Sep;54(9):2225-32. doi: 10.1128/JCM.03395-15.

de la Cruz M, González I, Parish CA, et al. Production of Ramoplanin and Ramoplanin Analogs by Actinomycetes. Front Microbiol. 2017 Mar 6;8:343. doi: 10.3389/fmicb.2017.00343.

Duncan LR, Sader HS, Flamm RK, et al Oritavancin in vitro activity against contemporary Staphylococcus aureus isolates responsible for invasive community- and healthcare-associated infections among patients in the United States (2013-2014). Diagn Microbiol Infect Dis. 2016 Nov;86(3):303-6. doi: 10.1016/j.diagmicrobio.2016.07.025.

Esposito S, Bianchini S. Dalbavancin for the treatment of paediatric infectious diseases. Eur J Clin Microbiol Infect Dis. 2016 Dec;35(12):1895-901. doi: 10.1007/s10096-016-2756-z.

Fulco P, Wenzel RP. Ramoplanin: a topical lipoglycodepsipeptide antibacterial agent. Expert Rev Anti Infect Ther. 2006 Dec;4(6):939-45. doi: 10.1586/14787210.4.6.939.

Gao C, Uzelac I, Gottfries J, Eriksson LA. Exploration of multiple Sortase A protein conformations in virtual screening. Sci Rep. 2016 Feb 5;6:20413. doi: 10.1038/srep20413.

Hall EA, Kuru E, VanNieuwenhze MS. Solid-phase synthesis of lysobactin (katanosin B): insights into structure and function. Org Lett. 2012 Jun 1;14(11):2730-3. doi: 10.1021/ol300926d.

Hassoun A, Friedman B, Saravolatz LD. Telavancin in the recent Hospital acquired and Ventilator associated pneumonia (HAP/VAP) 2016 guideline. Clin Infect Dis. 2017 Mar 24. doi: 10.1093/cid/cix272.

He H, Williamson RT, Shen B, et al, Mannopeptimycins, novel antibacterial glycopeptides from Streptomyces hygroscopicus, LL-AC98. J Am Chem Soc. 2002 Aug 21;124(33):9729-36. PMID: 12175230.

Hou J, Robbel L, Marahiel MA. Identification and characterization of the lysobactin biosynthetic gene cluster reveals mechanistic insights into an unusual termination module architecture. Chem Biol. 2011 May 27;18(5):655-64. doi: 10.1016/j.chembiol.2011.02.012.

Jang KH, Chung SC, Shin J, et al. Aaptamines as sortase A inhibitors from the tropical sponge Aaptos aaptos. Bioorg Med Chem Lett. 2007 Oct 1;17(19):5366-9. doi: 10.1016/j.bmcl.2007.08.007.

Jeon JE, Na Z, Jung M, et al. Discorhabdins from the Korean marine sponge Sceptrella sp. J Nat Prod. 2010 Feb 26;73(2):258-62. doi: 10.1021/np9005629.

Jones RN, Farrell DJ, Flamm RK, et al. Surrogate analysis of vancomycin to predict susceptible categorization of dalbavancin. Diagn Microbiol Infect Dis. 2015 May;82(1):73-7. doi: 10.1016/j.diagmicrobio.2015.01.017.

Jones RN, Schuchert JE, Mendes RE. Dalbavancin Activity When Tested against Streptococcus pneumoniae Isolated in Medical Centers on Six Continents (2011 to 2014). Antimicrob Agents Chemother. 2016 May 23;60(6):3419-25. doi: 10.1128/AAC.00116-16.

Kalil AC, Murthy MH, Hermsen ED, et al. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis. Crit Care Med. 2010 Sep;38(9):1802-8. doi: 10.1097/CCM.0b013e3181eb3b96.

Kang SS, Kim JG, Lee TH, Oh KB. Flavonols inhibit sortases and sortase-mediated Staphylococcus aureus clumping to fibrinogen. Biol Pharm Bull. 2006 Aug;29(8):1751-5. PMID: 16880637.

Kim SH, Shin DS, Oh MN, et al. Inhibition of sortase, a bacterial surface protein anchoring transpeptidase, by beta-sitosterol-3-O-glucopyranoside from Fritillaria verticillata. Biosci Biotechnol Biochem. 2003 Nov;67(11):2477-9. doi: 10.1271/bbb.67.2477.

Klinker KP, Borgert SJ. Beyond Vancomycin: The Tail of the Lipoglycopeptides. Clin Ther. 2015 Dec 1;37(12):2619-36. doi: 10.1016/j.clinthera.2015.11.007.

Kruger RG, Dostal P, McCafferty DG. An economical and preparative orthogonal solid phase synthesis of fluorescein and rhodamine derivatized peptides: FRET substrates for the Staphylococcus aureus sortase SrtA transpeptidase reaction. Chem Commun (Camb). 2002 Sep 21;(18):2092-3. PMID: 12357793. doi: 10.1039/B206303D.

Labroli MA, Caldwell JP, Yang C, et al. Discovery of potent wall teichoic acid early stage inhibitors. Bioorg Med Chem Lett. 2016 Aug 15;26(16):3999-4002. doi: 10.1016/j.bmcl.2016.06.090.

Lee SH, Wang H, Labroli M, et al. TarO-specific inhibitors of wall teichoic acid biosynthesis restore β-lactam efficacy against methicillin-resistant staphylococci. Sci Transl Med. 2016 Mar 9;8(329):329ra32. doi: 10.1126/scitranslmed.aad7364.

Lee W, Schaefer K, Qiao Y, et al. The Mechanism of Action of Lysobactin. J Am Chem Soc. 2016 Jan 13;138(1):100-3. doi: 10.1021/jacs.5b11807.

Lehoux D, Ostiguy V, Cadieux C, et al. Oritavancin Pharmacokinetics and Bone Penetration in Rabbits. Antimicrob Agents Chemother. 2015 Oct;59(10):6501-5. doi: 10.1128/AAC.00981-15.

Li W, Fan Z, Geng K, et al. Late-stage diversification of biologically active pyridazinones via a direct C-H functionalization strategy. Org Biomol Chem. 2015 Jan 14;13(2):539-48. doi: 10.1039/c4ob02061h.

Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015 Jan 22;517(7535):455-9. doi: 10.1038/nature14098.

Liu B, Chen F, Bi C, et al. Quercitrin, an inhibitor of Sortase A, interferes with the adhesion of Staphylococcal aureus. Molecules. 2015 Apr 13;20(4):6533-43. doi: 10.3390/molecules20046533.

Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012 Mar;18(3):268-81. doi: 10.1111/j.1469-0691.2011.03570.x.

Maresso AW, Wu R, Kern JW, et al. Activation of inhibitors by sortase triggers irreversible modification of the active site. J Biol Chem. 2007 Aug 10;282(32):23129-39. doi: 10.1074/jbc.M701857200.

Mathur H, Rea MC, Cotter PD, et al. The potential for emerging therapeutic options for Clostridium difficile infection. Gut Microbes. 2014;5(6):696-710. doi: 10.4161/19490976.2014.983768.

Mendes RE, Farrell DJ, Sader HS, Jones RN. Oritavancin microbiologic features and activity results from the surveillance program in the United States. Clin Infect Dis. 2012 Apr;54 Suppl 3:S203-13. doi: 10.1093/cid/cir923.

Mendes RE, Farrell DJ, Sader HS, et al. Update of the telavancin activity in vitro tested against a worldwide collection of Gram-positive clinical isolates (2013), when applying the revised susceptibility testing method. Diagn Microbiol Infect Dis. 2015 Apr;81(4):275-9. doi: 10.1016/j.diagmicrobio.2014.12.011.

Nannini EC, Corey GR, Stryjewski ME. Telavancin for the treatment of hospital-acquired pneumonia: findings from the ATTAIN studies. Expert Rev Anti Infect Ther. 2012 Aug;10(8):847-54. doi: 10.1586/eri.12.81.

Ng V, Chan WC. New Found Hope for Antibiotic Discovery: Lipid II Inhibitors. Chemistry. 2016 Aug 26;22(36):12606-16. doi: 10.1002/chem.201601315.

O’Connor RD, Singh M, Chang J, et al. Dual Mode of Action for Plusbacin A3 in Staphylococcus aureus. J Phys Chem B. 2017 Feb Chang 23;121(7):1499-1505. doi: 10.1021/acs.jpcb.6b11039.

Oh I, Yang WY, Chung SC, et al. In vitro sortase A inhibitory and antimicrobial activity of flavonoids isolated from the roots of Sophora flavescens. Arch Pharm Res. 2011 Feb;34(2):217-22. doi: 10.1007/s12272-011-0206-0.

Oh KB, Mar W, Kim S, et al. Bis(indole) alkaloids as sortase A inhibitors from the sponge Spongosorites sp. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4927-31. doi: 10.1016/j.bmcl.2005.08.021.

Oh KB, Kim SH, Lee J, et al Discovery of diarylacrylonitriles as a novel series of small molecule sortase A inhibitors. J Med Chem. 2004 May 6;47(10):2418-21. doi: 10.1021/jm0498708.

Oh KB, Oh MN, Kim JG, et al. Inhibition of sortase-mediated Staphylococcus aureus adhesion to fibronectin via fibronectin-binding protein by sortase inhibitors. Appl Microbiol Biotechnol. 2006 Mar;70(1):102-6. PMID: 16010573. doi: 10.1007/s00253-005-0040-8.

Oh KB, Nam KW, Ahn H, et al. Therapeutic effect of (Z)-3-(2,5-dimethoxyphenyl)-2-(4-methoxyphenyl) acrylonitrile (DMMA) against Staphylococcus aureus infection in a murine model. Biochem Biophys Res Commun. 2010 May 28;396(2):440-4. doi: 10.1016/j.bbrc.2010.04.113.

Outterson K, Rex JH, Jinks T, et al. Accelerating global innovation to address antibacterial resistance: introducing CARB-X. Nat Rev Drug Discov. 2016 Sep;15(9):589-90. doi: 10.1038/nrd.2016.155.

Paganelli FL, van de Kamer T, Brouwer EC, et al. Lipoteichoic acid synthesis inhibition in combination with antibiotics abrogates growth of multidrug-resistant Enterococcus faecium. Int J Antimicrob Agents. 2017 Mar;49(3):355-363. doi: 10.1016/j.ijantimicag.2016.12.002.

Park BS, Kim JG, Kim MR, et al. Curcuma longa L. constituents inhibit sortase A and Staphylococcus aureus cell adhesion to fibronectin. J Agric Food Chem. 2005 Nov 16;53(23):9005-9. PMID: 16277395. doi: 10.1021/jf051765z.

Parmar A, Prior SH, Iyer A, et al. Defining the molecular structure of teixobactin analogues and understanding their role in antibacterial activities. Chem Commun (Camb). 2017 Feb 7;53(12):2016-2019. doi: 10.1039/c6cc09490b.

Peromet M, Schoutens E, Yourassowsky E. Clinical and microbiological study of enduracidin in infections due to methicillin-resistant strains of Staphylococcus aureus. Chemotherapy. 1973;19(1):53-61. PMID: 4490722. doi: 10.1159/000221439.

Purrello SM, Garau J, Giamarellos E, et al. Methicillin-resistant Staphylococcus aureus infections: A review of the currently available treatment options. J Glob Antimicrob Resist. 2016 Dec;7:178-186. doi: 10.1016/j.jgar.2016.07.010.

Rentero Rebollo I, McCallin S, Bertoldo D, et al. Development of Potent and Selective S. aureus Sortase A Inhibitors Based on Peptide Macrocycles. ACS Med Chem Lett. 2016 Apr 14;7(6):606-11. doi: 10.1021/acsmedchemlett.6b00045.

Richter SG, Elli D, Kim HK, et al. Small molecule inhibitor of lipoteichoic acid synthesis is an antibiotic for Gram-positive bacteria. Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3531-6. doi: 10.1073/pnas.1217337110.

Scott CJ, McDowell A, Martin SL, et al. Irreversible inhibition of the bacterial cysteine protease-transpeptidase sortase (SrtA) by substrate-derived affinity labels. Biochem J. 2002 Sep 15;366(Pt 3):953-8. doi: 10.1042/BJ20020602.

Shoji J, Hinoo H, Katayama T, et al. Structures of new peptide antibiotics, plusbacins A1-A4 and B1-B4. J Antibiot (Tokyo). 1992 Jun;45(6):824-31. doi: 10.7164/antibiotics.45.824. PMID: 1500346.

Song M, Teng Z, Li M, et al. Epigallocatechin gallate inhibits Streptococcus pneumoniae virulence by simultaneously targeting pneumolysin and sortase A. J Cell Mol Med. 2017 Apr 12. doi: 10.1111/jcmm.13179.

Stewart CL, Turner MS, Frens JJ, et al. Real-World Experience with Oritavancin Therapy in Invasive Gram-Positive Infections. Infect Dis Ther. 2017 Jun;6(2):227-89. doi: 10.1007/s40121-017-0156-z.

Tanayama S, Fugono T, Yamazaki T. Enduracidin, a new antibiotic. IV. The fate of enduracidin administered parenterally into rabbits. J Antibiot (Tokyo). 1968 May;21(5):313-9. PMID: 5726287.

Uddin R, Lodhi MU, Ul-Haq Z. Combined pharmacophore and 3D-QSAR study on a series of Staphylococcus aureus Sortase A inhibitors. Chem Biol Drug Des. 2012 Aug;80(2):300-14. doi: 10.1111/j.1747-0285.2012.01403.x.

Van Bambeke F. Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review. Drugs. 2015 Dec;75(18):2073-95. doi: 10.1007/s40265-015-0505-8.

van Harten RM, Willems RJ, Martin NI, Hendrickx AP. Multidrug-Resistant Enterococcal Infections: New Compounds, Novel Antimicrobial Therapies? Trends Microbiol. 2017 Jun;25(6):467-79. pii: S0966-842X(17)30016-1. doi: 10.1016/j.tim.2017.01.004.

Welte T, Pletz MW. Antimicrobial treatment of nosocomial meticillin-resistant Staphylococcus aureus (MRSA) pneumonia: current and future options. Int J Antimicrob Agents. 2010 Nov;36(5):391-400. doi: 10.1016/j.ijantimicag.2010.06.045.

Wohlrab A, Lamer R, VanNieuwenhze MS. Total synthesis of plusbacin A3: a depsipeptide antibiotic active against vancomycin-resistant bacteria. J Am Chem Soc. 2007 Apr 11;129(14):4175-7. doi: 10.1021/ja068455x.

Wu MC, Styles MQ, Law BJ, et al. Engineered biosynthesis of enduracidin lipoglycopeptide antibiotics using the ramoplanin mannosyltransferase Ram29. Microbiology. 2015 Jul;161(7):1338-47. doi: 10.1099/mic.0.000095.

Yang H, Chen KH, Nowick JS. Elucidation of the Teixobactin Pharmacophore. ACS Chem Biol. 2016 Jul 15;11(7):1823-6. doi: 10.1021/acschembio.6b00295.

Yarlagadda V, Sarkar P, Samaddar S, Haldar J. A Vancomycin Derivative with a Pyrophosphate-Binding Group: A Strategy to Combat Vancomycin-Resistant Bacteria. Angew Chem Int Ed Engl. 2016 Jun 27;55(27):7836-40. doi: 10.1002/anie.201601621.

Yarlagadda V, Sarkar P, Manjunath GB, Haldar J. Lipophilic vancomycin aglycon dimer with high activity against vancomycin-resistant bacteria. Bioorg Med Chem Lett. 2015 Dec 1;25(23):5477-80. doi: 10.1016/j.bmcl.2015.10.083.

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