Antimicrobial Resistance and Antibacterial Discovery 2 [CAN IGNORE]

Why is antimicrobial research more important and urgent now?

Due to rising antimicrobial resistance and lack of new effective antibiotics"

What is phenotype-based drug discovery?

Screening whole cells to find active compounds before identifying the target"

What is the main advantage of phenotype-based screening?

Target is linked to a biological response, increasing novelty and druggability"

What is target-based drug discovery?

Identifying compounds that bind to a known bacterial target with high affinity"

What is a key limitation of target-based discovery in antibiotics?

Compounds may not enter bacteria or are pumped out, causing a discovery void"

Why are gram-negative bacteria harder to treat with antibiotics?

They have an outer LPS membrane and efflux pumps that block or expel drugs"

Why are gram-positive bacteria easier to target with antibiotics?

They lack the outer LPS membrane barrier present in gram-negatives"

What are major challenges in antibacterial drug discovery?

Knowledge gaps, low funding, poor revenue, and limited commercial incentives"

What defines a good antibacterial drug target?

Present in pathogens, absent in humans, essential for growth, and known function"

Why must antibacterial targets be absent in humans?

To reduce the risk of human toxicity"

Why should antibacterial targets be essential for bacterial growth?

To prevent bacteria from mutating to bypass the target"

Why might 'essential' genes not always make good drug targets?

Because partial inhibition may not affect bacterial survival"

What are key mechanisms of antibacterial action?

Cell wall synthesis inhibition, membrane disruption, DNA synthesis inhibition, and protein synthesis inhibition"

Why should target-based screening be avoided in antibiotic discovery?

It may find compounds that can't penetrate bacterial membranes"

What is modified phenotype-based discovery?

A structured approach starting with whole cell screening and ending with clinical candidate evaluation"

What is the first step in modified phenotype-based discovery?

Identify new chemical classes via whole cell screening"

Why is the antibiotic discovery market underfunded?

Low profitability, acute diseases, generic competition, and market saturation"

Why do pharma companies prefer chronic diseases over infections?

Chronic conditions generate more revenue due to long treatment durations"

How does resistance affect the use of new antibiotics?

Clinicians avoid prescribing new drugs to preserve them, limiting market success"

Who mainly conducts antibiotic discovery today?

Small and medium-sized enterprises and academic institutions"

Why do large companies contribute little to antibiotic discovery?

High cost, low profit, and risk-averse business models"

What is the PEW Charitable Trusts' role in antibiotic discovery?

Launched a five-year plan to revive antibacterial drug discovery"

What is the focus of the catalytic phase in PEW's plan?

Sharing gram-negative drug entry and efflux knowledge and promoting collaboration"

What is the main challenge in sharing antibiotic discovery knowledge?

Most data, especially failures, is not published and remains in industry"

What is the goal of the pilot phase of PEW's plan?

Develop tools for measuring drug penetration and explore resistance-breaking combinations"

What happens in the implementation phase of PEW's plan?

Scale up focused chemical libraries and support novel therapies to clinical stage"

What is the rationale behind combination antibiotic therapy?

Targets multiple pathways, reducing the chance of resistance"

Why is combination therapy effective in treating TB?

It attacks bacteria through multiple mechanisms, limiting resistance development"

What is the Waksman revival approach?

Exploring uncultured microorganisms to discover new antibiotics"

What is the Teixobactin study known for?

Culturing previously unculturable bacteria to discover novel antibiotics"

What are prodrugs in antibiotic discovery?

Inactive compounds activated by bacterial enzymes once inside the cell"

How do prodrugs benefit antibacterial therapy?

Allow targeted delivery, reduce resistance pressure, and enable narrow-spectrum activity"

What is the advantage of narrow-spectrum antibiotics?

They target specific species and preserve beneficial bacteria"

What are the rules of penetration in antibiotic discovery?

Chemical features enabling compounds to cross gram-negative membranes"

Why did past HTS campaigns fail in antibiotic discovery?

Compounds couldn't penetrate bacteria despite binding to targets"

How can rules of penetration improve HTS platforms?

Enable screening of compounds that can both bind targets and penetrate bacteria"

What are the benefits of designing antibiotics with penetration rules?

Improved entry, resistance avoidance, and intracellular activity"

How do rules of penetration influence rational drug design?

Guide the design of effective compounds that overcome bacterial barriers"

How can rules of penetration revive narrow-spectrum antibiotics?

By optimizing them for improved entry and efficacy in resistant strains"

Why is it difficult to profit from new antibiotics?

Short treatment durations, resistance, and competition from generics"

Why are new class antibiotics more prone to eventual resistance?

Bacteria adapt and accumulate resistance traits over time"

How does resistance knowledge pass through bacterial generations?

Through genetic accumulation, making newer strains more resistant"