Staph Wars: the Antibiotic Pipeline Strikes Back

Overview

Journal Microbiology (Reading)

Specialty Microbiology

Date 2023 Sep 1

PMID 37656158

Authors

Edward J A Douglas

Maisem Laabei

Affiliations

Soon will be listed here.

Abstract

Antibiotic chemotherapy is widely regarded as one of the most significant medical advancements in history. However, the continued misuse of antibiotics has contributed to the rapid rise of antimicrobial resistance (AMR) globally. , a major human pathogen, has become synonymous with multidrug resistance and is a leading antimicrobial-resistant pathogen causing significant morbidity and mortality worldwide. This review focuses on (1) the targets of current anti-staphylococcal antibiotics and the specific mechanisms that confirm resistance; (2) an in-depth analysis of recently licensed antibiotics approved for the treatment of infections; and (3) an examination of the pre-clinical pipeline of anti-staphylococcal compounds. In addition, we examine the molecular mechanism of action of novel antimicrobials and derivatives of existing classes of antibiotics, collate data on the emergence of resistance to new compounds and provide an overview of key data from clinical trials evaluating anti-staphylococcal compounds. We present several successful cases in the development of alternative forms of existing antibiotics that have activity against multidrug-resistant . Pre-clinical antimicrobials show promise, but more focus and funding are required to develop novel classes of compounds that can curtail the spread of and sustainably control antimicrobial-resistant infections.

Citing Articles

Potential Therapeutic Targets for Combination Antibody Therapy Against Infections.

Ke S, Kil H, Roggy C, Shields T, Quinn Z, Quinn A Antibiotics (Basel). 2024; 13(11).

PMID: 39596740 PMC: 11591076. DOI: 10.3390/antibiotics13111046.

Engineering Whole-Cell Biosensors for Enhanced Detection of Environmental Antibiotics Using a Synthetic Biology Approach.

Priyadharshini A, Ganesh I, Rangarajalu K, Samuel M, Ravikumar S Indian J Microbiol. 2024; 64(2):402-408.

PMID: 39010990 PMC: 11246489. DOI: 10.1007/s12088-024-01259-w.

References

Gropper S, Albareda N, Chelius K, Kruger D, Mitha I, Vahed Y . Ozenoxacin 1% cream in the treatment of impetigo: a multicenter, randomized, placebo- and retapamulin-controlled clinical trial. Future Microbiol. 2014; 9(9):1013-23. DOI: 10.2217/fmb.14.78. View

Hammes W, Neuhaus F . On the mechanism of action of vancomycin: inhibition of peptidoglycan synthesis in Gaffkya homari. Antimicrob Agents Chemother. 1974; 6(6):722-8. PMC: 444726. DOI: 10.1128/AAC.6.6.722. View

Isaksson J, Brandsdal B, Engqvist M, Flaten G, Mjoen Svendsen J, Stensen W . A synthetic antimicrobial peptidomimetic (LTX 109): stereochemical impact on membrane disruption. J Med Chem. 2011; 54(16):5786-95. DOI: 10.1021/jm200450h. View

Honeyman L, Ismail M, Nelson M, Bhatia B, Bowser T, Chen J . Structure-activity relationship of the aminomethylcyclines and the discovery of omadacycline. Antimicrob Agents Chemother. 2015; 59(11):7044-53. PMC: 4604364. DOI: 10.1128/AAC.01536-15. View

Macone A, Caruso B, Leahy R, Donatelli J, Weir S, Draper M . In vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline. Antimicrob Agents Chemother. 2013; 58(2):1127-35. PMC: 3910882. DOI: 10.1128/AAC.01242-13. View

Abat C, Fournier P, Jimeno M, Rolain J, Raoult D . Extremely and pandrug-resistant bacteria extra-deaths: myth or reality?. Eur J Clin Microbiol Infect Dis. 2018; 37(9):1687-1697. DOI: 10.1007/s10096-018-3300-0. View

Dalhoff A, Stubbings W, Schubert S . Comparative in vitro activities of the novel antibacterial finafloxacin against selected Gram-positive and Gram-negative bacteria tested in Mueller-Hinton broth and synthetic urine. Antimicrob Agents Chemother. 2011; 55(4):1814-8. PMC: 3067158. DOI: 10.1128/AAC.00886-10. View

Lipka M, Filipek R, Bochtler M . Crystal structure and mechanism of the Staphylococcus cohnii virginiamycin B lyase (Vgb). Biochemistry. 2008; 47(14):4257-65. DOI: 10.1021/bi7015266. View

Boucher H, Wilcox M, Talbot G, Puttagunta S, Das A, Dunne M . Once-weekly dalbavancin versus daily conventional therapy for skin infection. N Engl J Med. 2014; 370(23):2169-79. DOI: 10.1056/NEJMoa1310480. View

10.

Stefani S, Bongiorno D, Mongelli G, Campanile F . Linezolid Resistance in Staphylococci. Pharmaceuticals (Basel). 2016; 3(7):1988-2006. PMC: 4036669. DOI: 10.3390/ph3071988. View

11.

Hot C, Berthet N, Chesneau O . Characterization of sal(A), a novel gene responsible for lincosamide and streptogramin A resistance in Staphylococcus sciuri. Antimicrob Agents Chemother. 2014; 58(6):3335-41. PMC: 4068490. DOI: 10.1128/AAC.02797-13. View

12.

Miller L, Fowler V, Shukla S, Rose W, Proctor R . Development of a vaccine against Staphylococcus aureus invasive infections: Evidence based on human immunity, genetics and bacterial evasion mechanisms. FEMS Microbiol Rev. 2019; 44(1):123-153. PMC: 7053580. DOI: 10.1093/femsre/fuz030. View

13.

Novak R, Shlaes D . The pleuromutilin antibiotics: a new class for human use. Curr Opin Investig Drugs. 2010; 11(2):182-91. View

14.

Candiani G, Abbondi M, Borgonovi M, Romano G, Parenti F . In-vitro and in-vivo antibacterial activity of BI 397, a new semi-synthetic glycopeptide antibiotic. J Antimicrob Chemother. 1999; 44(2):179-92. DOI: 10.1093/jac/44.2.179. View

15.

Zimmerli W, Widmer A, Blatter M, Frei R, Ochsner P . Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA. 1998; 279(19):1537-41. DOI: 10.1001/jama.279.19.1537. View

16.

Eyal Z, Matzov D, Krupkin M, Wekselman I, Paukner S, Zimmerman E . Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus. Proc Natl Acad Sci U S A. 2015; 112(43):E5805-14. PMC: 4629319. DOI: 10.1073/pnas.1517952112. View

17.

Tenson T, Lovmar M, Ehrenberg M . The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. J Mol Biol. 2003; 330(5):1005-14. DOI: 10.1016/s0022-2836(03)00662-4. View

18.

Kaatz G, DeMarco C, Seo S . MepR, a repressor of the Staphylococcus aureus MATE family multidrug efflux pump MepA, is a substrate-responsive regulatory protein. Antimicrob Agents Chemother. 2006; 50(4):1276-81. PMC: 1426934. DOI: 10.1128/AAC.50.4.1276-1281.2006. View

19.

Piller P, Wolinski H, Cordfunke R, Drijfhout J, Keller S, Lohner K . Membrane Activity of LL-37 Derived Antimicrobial Peptides against : Superiority of SAAP-148 over OP-145. Biomolecules. 2022; 12(4). PMC: 9028586. DOI: 10.3390/biom12040523. View

20.

Leighton A, Gottlieb A, Dorr M, Jabes D, Mosconi G, VanSaders C . Tolerability, pharmacokinetics, and serum bactericidal activity of intravenous dalbavancin in healthy volunteers. Antimicrob Agents Chemother. 2004; 48(3):940-5. PMC: 353075. DOI: 10.1128/AAC.48.3.940-945.2004. View