Structural biology of the fatty acid biosynthesis (FASII) pathway of pathogenic Neisseria: a promising target for combating emerging drug resistance

Jeffrey Nanson

Research output: ThesisDoctoral Thesis

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Abstract

Neisseria is a large genus of Proteobacteria that colonize the mucosal surfaces of both humans and animals. Most Neisseria spp. are considered to be non-pathogenic commensal bacteria, with only Neisseria gonorrhoeae and Neisseria meningitidis being regarded as human pathogens. Despite sharing a large number of genes and virulence factors, these two closely related obligate human pathogens cause distinctive diseases.

Gonorrhoea is a sexually transmissible infection caused by the bacterium Neisseria gonorrhoea. This infection is of major health concern due to high rates of disease, and rapidly diminishing treatment options due to drug resistance. Ceftriaxone is the current first line treatment in most countries, with no identified ideal alternative. The emergence of multiple drug resistant (MDR) strains with decreased sensitivity to ceftriaxone has been reported in many countries, including Australia. Reports of MDR strains of N. gonorrhoeae resistant to ceftriaxone, termed extensively drug resistant (XDR), have caused considerable alarm. The World Health Organisation has issued a Global Action
Plan to minimise the spread and impact of antimicrobial resistance in N. gonorrhoeae, calling for the development of new treatments as an urgent priority. In 2013, the USA Centres for Disease Control and Prevention classified N. gonorrhoeae drug resistance in the top three of antibiotic resistance threats. There are no vaccines available for prevention of N. gonorrhoeae infections, thus the current treatment is antibiotic therapy. With no ideal alternative treatment or vaccine available, it is widely feared that gonorrhoea will become untreatable.

Antimicrobial resistance in N. meningitidis, the causative agent of debilitating and potentially fatal meningococcal meningitis, also appears to be increasing. Whilst not as prevalent as in N. gonorrhoeae, resistance to penicillins, rifampicin, tetrayclines, and sulphonamides is now widely reported in N. meningitidis, with at least one reported case of N. meningitidis displaying reduced susceptibility to the extended-spectrum cephalosporins ceftriaxone and cefotaxime. The drug resistance displayed by these pathogenic bacteria demonstrates an urgent need for development of new antimicrobial agents.

The fatty acid synthesis type II (FASII) enzymes of N. gonorrhoeae and N. meningitidis, responsible for lipid biogenesis, represent an attractive target for the development of new antimicrobials. Triclosan, a widely used antibacterial, inhibits this pathway, and demonstrates the validity of enzymes of the FASII pathway as drug targets. To provide a strong platform for the development of urgently needed antimicrobials, the three-dimensional structures of the FASII enzymes ACP synthase, FabD, FabF, FabG, FabH, and FabI from N. meningitidis (98-100% identity to those of N. gonorrhoeae) were solved by X-ray crystallography. Significantly, the FASII reductases FabG and FabI are inhibited by the plant polyphenol epigallocatechin gallate (EGCG), thus the structures of FabI in complex with EGCG, NADH, and NAD:triclosan, and FabG in complex with NADPH, were also determined, providing detailed knowledge of the active and co-factor binding sites within both enzymes. The binding sites for EGCG and NADH in FabI appear highly similar to those in FabG, possibly providing a basis for the design of antimicrobials that simultaneously target both enzymes, and are suitable for the treatment of drug resistant N. gonorrhoeae and N. meningitidis.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Charles Sturt University
Supervisors/Advisors
  • Forwood, Jade, Principal Supervisor
Place of PublicationAustralia
Publisher
Publication statusPublished - 2015

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Neisseria
Neisseria gonorrhoeae
Drug Resistance
Neisseria meningitidis
Fatty Acids
Ceftriaxone
NAD
Triclosan
Enzymes
Pharmaceutical Preparations
Gonorrhea
Bacteria
Vaccines
Infection
Binding Sites
Meningococcal Meningitis
Penicillin Resistance
Proteobacteria
Cefotaxime
X Ray Crystallography

Cite this

@phdthesis{47e6f0dc4144420a94beec7b4f17d381,
title = "Structural biology of the fatty acid biosynthesis (FASII) pathway of pathogenic Neisseria: a promising target for combating emerging drug resistance",
abstract = "Neisseria is a large genus of Proteobacteria that colonize the mucosal surfaces of both humans and animals. Most Neisseria spp. are considered to be non-pathogenic commensal bacteria, with only Neisseria gonorrhoeae and Neisseria meningitidis being regarded as human pathogens. Despite sharing a large number of genes and virulence factors, these two closely related obligate human pathogens cause distinctive diseases.Gonorrhoea is a sexually transmissible infection caused by the bacterium Neisseria gonorrhoea. This infection is of major health concern due to high rates of disease, and rapidly diminishing treatment options due to drug resistance. Ceftriaxone is the current first line treatment in most countries, with no identified ideal alternative. The emergence of multiple drug resistant (MDR) strains with decreased sensitivity to ceftriaxone has been reported in many countries, including Australia. Reports of MDR strains of N. gonorrhoeae resistant to ceftriaxone, termed extensively drug resistant (XDR), have caused considerable alarm. The World Health Organisation has issued a Global ActionPlan to minimise the spread and impact of antimicrobial resistance in N. gonorrhoeae, calling for the development of new treatments as an urgent priority. In 2013, the USA Centres for Disease Control and Prevention classified N. gonorrhoeae drug resistance in the top three of antibiotic resistance threats. There are no vaccines available for prevention of N. gonorrhoeae infections, thus the current treatment is antibiotic therapy. With no ideal alternative treatment or vaccine available, it is widely feared that gonorrhoea will become untreatable.Antimicrobial resistance in N. meningitidis, the causative agent of debilitating and potentially fatal meningococcal meningitis, also appears to be increasing. Whilst not as prevalent as in N. gonorrhoeae, resistance to penicillins, rifampicin, tetrayclines, and sulphonamides is now widely reported in N. meningitidis, with at least one reported case of N. meningitidis displaying reduced susceptibility to the extended-spectrum cephalosporins ceftriaxone and cefotaxime. The drug resistance displayed by these pathogenic bacteria demonstrates an urgent need for development of new antimicrobial agents.The fatty acid synthesis type II (FASII) enzymes of N. gonorrhoeae and N. meningitidis, responsible for lipid biogenesis, represent an attractive target for the development of new antimicrobials. Triclosan, a widely used antibacterial, inhibits this pathway, and demonstrates the validity of enzymes of the FASII pathway as drug targets. To provide a strong platform for the development of urgently needed antimicrobials, the three-dimensional structures of the FASII enzymes ACP synthase, FabD, FabF, FabG, FabH, and FabI from N. meningitidis (98-100{\%} identity to those of N. gonorrhoeae) were solved by X-ray crystallography. Significantly, the FASII reductases FabG and FabI are inhibited by the plant polyphenol epigallocatechin gallate (EGCG), thus the structures of FabI in complex with EGCG, NADH, and NAD:triclosan, and FabG in complex with NADPH, were also determined, providing detailed knowledge of the active and co-factor binding sites within both enzymes. The binding sites for EGCG and NADH in FabI appear highly similar to those in FabG, possibly providing a basis for the design of antimicrobials that simultaneously target both enzymes, and are suitable for the treatment of drug resistant N. gonorrhoeae and N. meningitidis.",
author = "Jeffrey Nanson",
year = "2015",
language = "English",
publisher = "Charles Sturt University",
address = "Australia",
school = "Charles Sturt University",

}

Structural biology of the fatty acid biosynthesis (FASII) pathway of pathogenic Neisseria : a promising target for combating emerging drug resistance. / Nanson, Jeffrey.

Australia : Charles Sturt University, 2015. 215 p.

Research output: ThesisDoctoral Thesis

TY - THES

T1 - Structural biology of the fatty acid biosynthesis (FASII) pathway of pathogenic Neisseria

T2 - a promising target for combating emerging drug resistance

AU - Nanson, Jeffrey

PY - 2015

Y1 - 2015

N2 - Neisseria is a large genus of Proteobacteria that colonize the mucosal surfaces of both humans and animals. Most Neisseria spp. are considered to be non-pathogenic commensal bacteria, with only Neisseria gonorrhoeae and Neisseria meningitidis being regarded as human pathogens. Despite sharing a large number of genes and virulence factors, these two closely related obligate human pathogens cause distinctive diseases.Gonorrhoea is a sexually transmissible infection caused by the bacterium Neisseria gonorrhoea. This infection is of major health concern due to high rates of disease, and rapidly diminishing treatment options due to drug resistance. Ceftriaxone is the current first line treatment in most countries, with no identified ideal alternative. The emergence of multiple drug resistant (MDR) strains with decreased sensitivity to ceftriaxone has been reported in many countries, including Australia. Reports of MDR strains of N. gonorrhoeae resistant to ceftriaxone, termed extensively drug resistant (XDR), have caused considerable alarm. The World Health Organisation has issued a Global ActionPlan to minimise the spread and impact of antimicrobial resistance in N. gonorrhoeae, calling for the development of new treatments as an urgent priority. In 2013, the USA Centres for Disease Control and Prevention classified N. gonorrhoeae drug resistance in the top three of antibiotic resistance threats. There are no vaccines available for prevention of N. gonorrhoeae infections, thus the current treatment is antibiotic therapy. With no ideal alternative treatment or vaccine available, it is widely feared that gonorrhoea will become untreatable.Antimicrobial resistance in N. meningitidis, the causative agent of debilitating and potentially fatal meningococcal meningitis, also appears to be increasing. Whilst not as prevalent as in N. gonorrhoeae, resistance to penicillins, rifampicin, tetrayclines, and sulphonamides is now widely reported in N. meningitidis, with at least one reported case of N. meningitidis displaying reduced susceptibility to the extended-spectrum cephalosporins ceftriaxone and cefotaxime. The drug resistance displayed by these pathogenic bacteria demonstrates an urgent need for development of new antimicrobial agents.The fatty acid synthesis type II (FASII) enzymes of N. gonorrhoeae and N. meningitidis, responsible for lipid biogenesis, represent an attractive target for the development of new antimicrobials. Triclosan, a widely used antibacterial, inhibits this pathway, and demonstrates the validity of enzymes of the FASII pathway as drug targets. To provide a strong platform for the development of urgently needed antimicrobials, the three-dimensional structures of the FASII enzymes ACP synthase, FabD, FabF, FabG, FabH, and FabI from N. meningitidis (98-100% identity to those of N. gonorrhoeae) were solved by X-ray crystallography. Significantly, the FASII reductases FabG and FabI are inhibited by the plant polyphenol epigallocatechin gallate (EGCG), thus the structures of FabI in complex with EGCG, NADH, and NAD:triclosan, and FabG in complex with NADPH, were also determined, providing detailed knowledge of the active and co-factor binding sites within both enzymes. The binding sites for EGCG and NADH in FabI appear highly similar to those in FabG, possibly providing a basis for the design of antimicrobials that simultaneously target both enzymes, and are suitable for the treatment of drug resistant N. gonorrhoeae and N. meningitidis.

AB - Neisseria is a large genus of Proteobacteria that colonize the mucosal surfaces of both humans and animals. Most Neisseria spp. are considered to be non-pathogenic commensal bacteria, with only Neisseria gonorrhoeae and Neisseria meningitidis being regarded as human pathogens. Despite sharing a large number of genes and virulence factors, these two closely related obligate human pathogens cause distinctive diseases.Gonorrhoea is a sexually transmissible infection caused by the bacterium Neisseria gonorrhoea. This infection is of major health concern due to high rates of disease, and rapidly diminishing treatment options due to drug resistance. Ceftriaxone is the current first line treatment in most countries, with no identified ideal alternative. The emergence of multiple drug resistant (MDR) strains with decreased sensitivity to ceftriaxone has been reported in many countries, including Australia. Reports of MDR strains of N. gonorrhoeae resistant to ceftriaxone, termed extensively drug resistant (XDR), have caused considerable alarm. The World Health Organisation has issued a Global ActionPlan to minimise the spread and impact of antimicrobial resistance in N. gonorrhoeae, calling for the development of new treatments as an urgent priority. In 2013, the USA Centres for Disease Control and Prevention classified N. gonorrhoeae drug resistance in the top three of antibiotic resistance threats. There are no vaccines available for prevention of N. gonorrhoeae infections, thus the current treatment is antibiotic therapy. With no ideal alternative treatment or vaccine available, it is widely feared that gonorrhoea will become untreatable.Antimicrobial resistance in N. meningitidis, the causative agent of debilitating and potentially fatal meningococcal meningitis, also appears to be increasing. Whilst not as prevalent as in N. gonorrhoeae, resistance to penicillins, rifampicin, tetrayclines, and sulphonamides is now widely reported in N. meningitidis, with at least one reported case of N. meningitidis displaying reduced susceptibility to the extended-spectrum cephalosporins ceftriaxone and cefotaxime. The drug resistance displayed by these pathogenic bacteria demonstrates an urgent need for development of new antimicrobial agents.The fatty acid synthesis type II (FASII) enzymes of N. gonorrhoeae and N. meningitidis, responsible for lipid biogenesis, represent an attractive target for the development of new antimicrobials. Triclosan, a widely used antibacterial, inhibits this pathway, and demonstrates the validity of enzymes of the FASII pathway as drug targets. To provide a strong platform for the development of urgently needed antimicrobials, the three-dimensional structures of the FASII enzymes ACP synthase, FabD, FabF, FabG, FabH, and FabI from N. meningitidis (98-100% identity to those of N. gonorrhoeae) were solved by X-ray crystallography. Significantly, the FASII reductases FabG and FabI are inhibited by the plant polyphenol epigallocatechin gallate (EGCG), thus the structures of FabI in complex with EGCG, NADH, and NAD:triclosan, and FabG in complex with NADPH, were also determined, providing detailed knowledge of the active and co-factor binding sites within both enzymes. The binding sites for EGCG and NADH in FabI appear highly similar to those in FabG, possibly providing a basis for the design of antimicrobials that simultaneously target both enzymes, and are suitable for the treatment of drug resistant N. gonorrhoeae and N. meningitidis.

M3 - Doctoral Thesis

PB - Charles Sturt University

CY - Australia

ER -