Antibacterials Flashcards
What are the THREE main antibacterial drug classes?
- Quinolones
- Penicillins
- Cephalosporins
For Quinolones;
A) What is the MOA?
B) What is the 2nd to 4th generation quinolones called
C) Which group is essential for antibacterial bioactivity?
A)
- Quinolones function as inhibitors of bacterial DNA GYRASE and/or TOPOISOMERASE IV –> essential enzymes in bacterial DNA replication, transcription and repair
B)
- Fluoroquinolones (F atom at ring C-6)
C)
- Carboxy-4-pyridone nucleus
For SAR studies of Quinolones
A) Which ring position are substituents not tolerated at?
B) Which ring position can affect drug potency and lipophilicity? It also requires a small alkyl unit for bioactivity.
C) Which ring position affects drug potency and lipophilicity? It can ONLY tolerate small groups such as CH3 or NH2.
D) Which ring position affects drug potency and lipophilicity? Bioactivity is increased with Fluoro (F) and leads to improved cell wall penetration.
E) Which ring position affects drug potency lipophilicity and the spectrum/range of antibacterial activity? It has a saturated dibasic N-containing heterocyclic group that serves as an extra ionic binding group to enhance/broaden activity. The introduction of a dibasic group leads to an amphoteric drug.
F) Which ring position affects drug potency, absorption and broadens the anaerobic activity? Usually X = C-R to allow for ring substituents as seen in the most recent drugs.
A)
- Not tolerated at position 2
B)
Position 1 (R1 at N-1)
C)
Position 5 (R5) –> infrequent site for substitution
D)
Position 6 (R6)
E)
Position 7 (R7)
F)
Position 8 (X = N, C-R8)
For 2nd generation quinolones;
A) What unit do the 6-fluoro drugs have that 1st generation quinolones don’t? How does this change their activity?
B) What do they show a broader spectrum of antibacterial activity of as a consequence of the group added in question A?
A)
- 6-Fluoro drugs that possess a simple 7-piperazine unit
- Compared to 1st gen drugs = improved gram-ve activity, lower protein binding and longer half-lives
B)
- due to 7-piperazine, they show a broader spectrum of antibacterial activity to include Pseudomonas and weak activity against Gram +ve Streptococci
For 3rd generation quinolones;
A) How do they vary from 2nd generation quinolones? Where do they introduce substituents?
B) How dos their activity change from 2nd generation quinolones?
A)
- Slightly more elaborated 7-piperazine unit
- Substituents at position 5/8 and shift away from N-1 ethyl substitution
- Shift away from N-1 ethyl substitution
B)
- Observe improved Gram -ve and +ve activity (most notably Streptococci) and broader activity to include atypicals
For 4th generation quinolones;
A) How do they vary from earlier generation quinolones? Where do they remove the substituent and where do they introduce new substituents?
B) How dos their activity change from earlier generation quinolones?
A)
- Possess a C-7 unit that isn’t piperazine rings, but instead, it is larger and highly substituted dibasic heterocyclics
- ALL lack a C-5 substituent
- Vast majority possess a small C-8 group and N-1 cyclopropyl unit
B)
- Display improved Gram -ve/+ve activity and significantly broader activity with anaerobic coverage
What are the polyvalent metal cations that quinolone drugs bind/chelate to? What is the result of this? Also include how to avoid this.
- ALL the quinolone drugs can bind/chelate to numerous polyvalent metal cations e.g. Ca2+ , Mg2+ , Fe2+ , Cu2+ and Al3+. Form complexes with carboxylic acid and keto group.
- Metal chelation results in the formation of low potency complexes with reduced drug absorption. Also displays poor aqueous solubility
- To avoid this, drugs should not be co-administered with diary products (Ca2+ rich), antiacids (contain Ca2+, Mg2+, Al3+, carbonates) and mineral supplements/tonics (contain various ions)
Which two groups may give rise to phototoxicity in ≥ 2nd generation quinolones?
Position 8 group. Alongside the 6-F group that is present after ≥ 2nd generation quinolones = drug instability and phototoxicity
What is the MOA of penicillins? What does this lead tp?
- IRREVERSIBLE inhibitors of TRANSPEPTIDASE (a key enzyme in bacterial cell wall biosynthesis)
- Leads to enzyme deactivation and cell wall defects that lead to bacterial cell lysis/death
For penicillins;
A) What does the C-2 C02H group represent?
B) Why is B-lactam ring vital for enzyme deactivation?
C) What does the instability/reactivity of B-lactam lead to?
A)
VITAL IONIC BINDING GROUP
B)
due to covalent reaction with a serine unit in the active site
C)
leads to various drug delivery and oral bioavailability issues
PENICILLIN DRUGS UNDERGO B-LACTAM DEGRADATION TO YIELD A RANGE OF INACTIVE DRUG DEGRADANTS. Why is this a concern?
Resulting in a major oral and aqueous delivery issues
> Many β-lactam antibacterials undergo extensive degradation within the GIT (notably gastric) impacts upon their oral delivery
What type of Hydrolysis are b-lactam drugs susceptible to?
Base, acid and/or enzymatic (lactamase) hydrolysis
(degraded at pH> 8 and pH<3)
For B-lactam ring hydrolytic stability;
A) Why is the B-lactam ring of the penam system prone to hydrolytic ring opening?
B) What shape is the bicyclic penam ? Why does this make it unstable?
C) How do all the above factors lead to low hydrolytic stability?
A)
- Ring strain and unstable amid bond
B)
- Bicyclic penam is V shaped leading to non-planar B-lactam ring with Amide C=O bond bent downwards and non-delocalized which makes it unstable
- Delocalisation (N-lone electron pair resonance into C=O) cannot occur as electrons don’t move around as they would do normally in an amide.
- Ionized form of the b-lactam is stable but it prefers to be in the unionized form due to non-planarity
C)
- Absence of lactam amide delocalization coupled with inherent strain observed for small 4-membered rings result in low hydrolytic stability of B-lactam drugs
For Hydrolytic stability of B-lactam drug;
A) How to improve acid/gastric/oral stability?
B) How does the answer to A improve the acid/gastric/oral availability
C) Does the answer to A make the drug less stable to hydrolysis?
D) Does the answer to A improve stability at higher pH?
E) What enymes are B-lactam drugs susceptible to hydrolytic deactivation by? Explain how they do this?
A)
- R-group in 6-amido unit must be a strong/potent EWG
B)
- Presence of a strong EWG disrupts the critical initial step within the acid hydrolysis pathway for β-lactam drugs
- PENICILLIN DRUG WITH R = STRONG EWG IS MORE ORALLY BIOACTIVE/BIOAVAILABLE AND USUALLY LESS SUSCEPTIBLE OR MORE SLOWLY DEGRADED IN STOMACH ACID/LOW pH
C)
- Yes, EWG makes 6-amide slightly less stable to hydrolysis
D)
- No, does not improve stability at higher alkaline pH
- Only improves stability for acid and gastric stability
E)
- Lactamase enzymes (a key factor in a bacterial resistance)
- Lactamases are bacterial enzymes that can dramatically improve bacterial survival by instigating β-lactam hydrolysis via a pathway that mimics the drug therapeutic MOA
How to overcome lactamase resistance? How to reduce the hydrolysis effects of b-lactamase?
- ‘BULKY’ R GROUP ON 6-ACYL SIDECHAIN CAN BE USED TO OVERCOME LACTAMASE i.e. ↑ LACTAMASE RESISTANCE
> R group = 2,6-DISUBSTITUTED PHENYL ring (prevents serine from attacking B-lactam ring)
- ALSO R GROUPS WHICH ‘STERICALLY SHIELD’ THE C=O OF THE B-LACTAM MAY REDUCE LACTAMASE HYDROLYSIS
General SAR summary of penicillins
SAR summary of cephalosporins
