Discovering novel antibiotics from Streptomyces
Lead Research Organisation:
University of East Anglia
Department Name: Graduate Office
Abstract
Natural products (NPs) from Streptomyces bacteria and their close relatives account for two thirds of the antibiotics currently used in human medicine but no new classes of antibiotic have been discovered since the 1980s. The UK Prime Minister David Cameron recently acknowledged that the shortage of new antibiotics threatens to take medicine back to the dark ages and the search for new antibiotics is now a global health priority.
For the last six years we have been searching for novel antibiotic-producing strains of bacteria in the nests of fungus growing (leafcutter) ants which live in South and Central America. This is an environmental niche that has not been explored before and it offers good prospects for the discovery of novel strains and antibiotics. The ants cut leaves to feed to a symbiotic fungus which they grow for food and they grow antibiotic-producing bacteria on their bodies to protect themselves and their fungus against infections.
The team has isolated > 400 strains of antibiotic-producing bacteria and started to characterise some of these strains in detail. One such strain is a new species of Streptomyces that produces at least two new classes of NP with novel chemical scaffolds. Analysis of the complete genome sequence of this strain suggests it makes several more novel NPs. In this project the successful applicant will use a combination of genome analysis, activity guided fractionation and natural products chemistry to characterise the novel NPs made by this Streptomyces strain and to identify the biosynthetic pathways and encoding gene clusters for each of these compounds. Novel NPs will be screened against multidrug resistant bacteria and fungi to identify lead compounds that may be useful in human medicine.
For the last six years we have been searching for novel antibiotic-producing strains of bacteria in the nests of fungus growing (leafcutter) ants which live in South and Central America. This is an environmental niche that has not been explored before and it offers good prospects for the discovery of novel strains and antibiotics. The ants cut leaves to feed to a symbiotic fungus which they grow for food and they grow antibiotic-producing bacteria on their bodies to protect themselves and their fungus against infections.
The team has isolated > 400 strains of antibiotic-producing bacteria and started to characterise some of these strains in detail. One such strain is a new species of Streptomyces that produces at least two new classes of NP with novel chemical scaffolds. Analysis of the complete genome sequence of this strain suggests it makes several more novel NPs. In this project the successful applicant will use a combination of genome analysis, activity guided fractionation and natural products chemistry to characterise the novel NPs made by this Streptomyces strain and to identify the biosynthetic pathways and encoding gene clusters for each of these compounds. Novel NPs will be screened against multidrug resistant bacteria and fungi to identify lead compounds that may be useful in human medicine.
Organisations
Publications
Holmes NA
(2018)
Complete genome sequence of Streptomyces formicae KY5, the formicamycin producer.
in Journal of biotechnology
McLean TC
(2019)
Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis.
in Antibiotics (Basel, Switzerland)
Qin Z
(2019)
A role for antibiotic biosynthesis monooxygenase domain proteins in fidelity control during aromatic polyketide biosynthesis.
in Nature communications
Qin Z
(2017)
Formicamycins, antibacterial polyketides produced by Streptomyces formicae isolated from African Tetraponera plant-ants.
in Chemical science
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011216/1 | 01/10/2015 | 31/03/2024 | |||
| 1654308 | Studentship | BB/M011216/1 | 01/10/2015 | 30/09/2019 | Rebecca Devine |
| Description | Antimicrobial resistance (AMR) poses a major risk to modern medicine, therefore finding new medicines is vital. Most currently used antibiotics are derived from the natural products of Actinomycete bacteria discovered more than half a century ago. We have isolated a novel Actinomycete, Streptomyces formicae, from the African plant-ant, Tetraponera penzigi, who use antibiotic-producing bacteria to farm their symbiotic fungus. By sequencing the S. formicae genome, we have shown that this "talented" strain contains gene clusters responsible for the production of as many as 45 secondary metabolites with antimicrobial activity. Under laboratory conditions, S. formicae produces compounds with activity against several clinically relevant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans and the multi-drug resistant fungus Lamentospora prolificans. This work has already identified a novel family of polyketide antibiotics, the formicamycins, which have in vitro activity against MRSA and vancomycin-resistant Enterococci (VRE). CRISPR/Cas9 was used to identify the producing gene cluster and to study the functions of most of the biosynthetic enzymes in the pathway, work that can be used to inform future drug discovery efforts. Novel, bioactive shunt metabolites from this pathway have also been isolated and studied as well as the regulatory networks responsible for antibiotic production in this strain. This work presents a significant step forward in the discovery of novel antimicrobial compounds. In addition, there is another antibacterial and an anti fungal compound produced by S. formicae, that also have significant bioactivity against drug-resistant isolates. We are now in the process of identifying the gene clusters that encode for these compounds in order to elucidate their structure for isolation and further study. |
| Exploitation Route | Others may use my research to develop novel antibiotics using the formicamycins as a basis. I have also developed the CRISPR/Cas9 genome editing technique for use in Streptomyces formicae that can be used for further genetic work. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Latitude Festival Tent |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | We had a stand in the kids area at latitude where we talked about antibiotics and resistance to both children and their parents. The children got the chance to plate their own samples from around the site, make an ant mask and take home a book. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Michael Mosley vs Superbugs |
| Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | We featured in a BBC 4 documentary about superbugs. I was filmed conducting lab work and my samples were used in experiments that were a main feature of the programme. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Norwich Science Festival |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | We had a stand at the Norwich Science festival about ants and antibiotics. |
| Year(s) Of Engagement Activity | 2016 |
| Description | Open days |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Undergraduate students |
| Results and Impact | We have a stand at the UEA open days discussing our research and other opportunities at UEA. |
| Year(s) Of Engagement Activity | 2015,2016,2017 |
| Description | School visits |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | We ran small workshops in classrooms with the children where we talked to them about antibiotics and resistance, and how we find new antibiotics. In some sessions, the children also got the chance to plate their own samples and we sent pictures of the incubated plates back to the teacher. |
| Year(s) Of Engagement Activity | 2015,2016,2017 |