GROUP THREE

• MATENDE HUSSEIN DPH/8548/171/DU

• NAKKAZI KIZZA JOAN DPH/8862/172/DU
• NANTONGO DOREEN DPH/8998/172/DU
• TWINOMUHANGI CALEB DPH/6630/163/DU
• HOPE CECILIA DPH/9083/172/DU
• NAGUJJA BABIRYE PATIENCE DPH/9082/172/
DU
• KAMUHANDA DANIEL DPH/8917/172/DU
• WANJALA PETER DPH/6130/162/DU
• KIKOMBERWA GEOFREY DPH/7077/163/DU
• JASSA FREDRICK DPH/6936/163/DU
 CARBAPENEMS
CLASSIFICATION
EARLY CARBAPENEMS
1. THIENAMYCIN
• Thienamycin is a novel -lactam antibiotic
first isolated from fermentation of cultures
of Streptomyces cattleya.
STRUCTURE OF THIENAMYCIN
• Two structural features of thienamycin
are shared with the penicillins and
cephalosporins:
• A fused bicyclic ring system containing a
beta-lactam.
• An equivalently attached 3-carboxyl group.
• The bicyclic system consists of a
carbapenem containing a double bond
between C-2 and C-3
Structure of thienamycin
 SAR of Thienamycin
 The double bond in the bicyclic structure creates
considerable ring strain and increases the reactivity of
the beta-lactam to ring opening reactions.
 A simple 1-hydroxyethyl group is essential(provides
resistance to lactamases).
 A 2-aminoethylthioether function at C-2.
At its optimally stable pH between 6 and 7
thienamycin undergoes concentration-dependent
inactivation. This inactivation is believed to result from
intermolecular aminolysis of the beta lactam by the
cysteamine side chain of a second molecules.
NB: Susceptibility to hydrolytic inactivation by renal
dehydropeptidase-1(DHP-1) which causes it to have an
unacceptably short half-life in vivo.
 2. IMIPENEM-CILASTATIN.

 Imipenem is N-formimidoylthienamycin, the

most successful of a series of chemically stable
derivatives of thienamycin in which the primary
amino group is converted to a nonnucleophilic
basic function.
 Cilastatin is an inhibitor of DHP-1
 Imipenem is very stable to most beta-
lactamases.
 It is an inhibitor of beta-lactamases from certain
Gram-negative bacteria resistant to other -beta
lactam antibiotics e.g. P. aeruginosa,
 IMIPENEM-CILASTATIN
• structure
 NEWER CARBAPENEMS:
• In the design of new carbapenems, structural
variations are being investigated in the objective of
developing analogs in advantage over imipenem.
• Improvements that are particularly desired include;
• Stability to hydrolysis catalysed by DHP-1.
• Stability to bacterial metallo-beta
lactamases(carbapenems) that hydrolyse imipenem.
• Activity against MRSA and increased potency
against P. aeruginosa especially imipenem resistant
strains.
• Enhanced PK properties such as oral bioavailability
and long duration of action, have therefore received
little emphasis in carbapenem analog design.
 NEWER CARABAPENEMS
a) MEROPENEM
Meropenem is a second-generation
carbapenem that, to date, has undergone the
most extensive clinical evaluation.
Meropenem exhibits greater potency against
Gram-negative and anaerobic bacteria than
does imipenem, but it is slightly less active
against most Gram-positive species.
Meropenem is not hydrolyzed by DHP-I and is
resistant to most B-lactamases.
STRUCTURE OF MEROPENEM
 b) BIAPENEM
• Biapenem is a newer second-generation
carbapenem with chemical and
microbiological properties similar to those
of meropenem.
• Biapenem is stable to DHP-I and resistant
to most B-lactamases.
• It is not active orally.
Structure of biapenem
SAR OF NEWER CARBAPENEM:
• Modifications, therefore have concentrated
on variations at positions 1 and 2 of the
carbapenem nucleus.
• The incoporation of a B-methyl group at the
position one gives the carbapenem stability
to hydrolysis by renal DHP-1.
• Substituents at the 2-position affects
primarily the spectrum of antibacterial
activity of carbapenem influencing
penetration into bacteria.
 SAR Contd
• The capability of carbapenems to exist as
zwitterionic structures ,resulting from the
combined features of a basic amine
function attached to the 2-position and 3-
carboxyl group, may enable these
carbapenems to enter bacteria via their
charged porin chanels.