▪ Abstract Formation of the bacterial division septum is catalyzed by a number of essential proteins that assemble into a ring structure at the future division site. Assembly of proteins into the c...

Bacterial Cell Division

β-LACTAM antibiotics (penicillins and cephalosporins) have attracted considerable attention as probes of cell growth and division1,2. Although extensive studies have been made on both penicillin-sensitive enzymes and penicillin binding proteins3, there has been no clear indication of the role of any of these components in the effects of β-lactam antibiotics on cell growth. We report the identification of a minor penicillin binding protein which we believe to be the target at which the amidinopenicillanic acid designated FL1060 (ref. 4) acts to affect the shape of Escherichia coli. This is the first example of the identification of a penicillin binding protein with an essential and defined role in bacterial cell growth.

Penicillin-binding proteins and cell shape in E. coli

This review focuses on the era of antibiosis that led to a better understanding of bacterial morphology, in particular the cell wall component peptidoglycan. This is an effort to take readers on a tour de force from the concept of antibiosis, to the serendipity of antibiotics, evolution of beta-lactam development, and the molecular biology of antibiotic resistance. These areas of research have culminated in a deeper understanding of microbiology, particularly in the area of bacterial cell wall synthesis and recycling. In spite of this knowledge, which has enabled design of new even more effective therapeutics to combat bacterial infection and has provided new research tools, antibiotic resistance remains a worldwide health care problem.

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Beta-lactam Antibiotics: From Antibiosis to Resistance and Bacteriology

INTRODUCTION ........................................................ 291 General ............... ......................................... 291 Cell Waill Structure and Synthesis ....................... ........................ 292 Identification of the Target of Penicillin Action .......... ........................ 293 PENICILLIN-BINDING COMPONENTS .............. .......................... 296 What Is Actually Bound? ....................................................... 298 How Much Penicillin Do Cells Bind? ................. ........................... 298 Is the Penicillin Bound Covalently? ................... .......................... 299 To What Group Does PenicillinBind?..... 299 Under What Conditions Can Penicillin Be Released from the PBCs?........ ........ 300 What Is the Physical Nature ofthe PBCs? ............. .......................... 300 Are PBCs Located in Peripheral Membranes, Mesosomes, or Both? ...... ........ 301 Do Organisms Have One or Multiple Proteins Which Bind Penicillin? ..... ...... 301 Isolation ofPBCs by Covalent Affinity Chromatography ........ ................. 303 What Is the Relationship of the PBCs to the Killing Site? ....... ................. 304 Biochemical Evidence for the Involvement ofPBCs in Peptidoglycan Synthesis . . 305 PENICILLIN-SENSITIVE ENZYMES ................ ........................... 306 Transpeptidase......................................................... 306 Transpeptidase assayed with natural acceptor in a coupled system ............ 306 Transpeptidase assayed with unnatural acceptor in a coupled system ..... ..... 307 Transpeptidase assayed in a simple, uncoupled system ....... ................. 307 D-Alanine Carboxypeptidase .................................................... 308 E. coli carboxypeptidase ...................................................... 309 Carboxypeptidases from Bacillus ................... .......................... 309 Streptomyces carboxypeptidases .................... .......................... 309 Endopeptidase......................................................... 313 Other Activities ........................................................ 314 Number of Enzymes Corresponding to the Different Penicillin-Sensitive Enzymatic Activities ........................................................ 314 Relationship ofthe Penicillin-Sensitive Enzymes to the PBCs ....... ............. 316 Physiological Functions ofthe Penicillin-Sensitive Enzymes ....... .............. 316 Physiological Evidence for the Existence of Multiple Transpeptidases ..... ...... 318 Kinetics of Penicillin Inhibition ................................................. 319 Models for the Interaction ofPenicillin with Its Target ........ .................. 321 MECHANISM OF KILLING BY PENICILLINS .......... ....................... 324 Mutant Analysis........................................................ 324 Evidence That Penicillin Kills by Inhibiting Cross-Linking ...................... 324 Killing by Amidino Penicillin ................................................... 325 Transfer of Penicillin Side Chain ................................................. 325 CONTROL OF CELL WALL SYNTHESIS ............. .......................... 326 SUMMARY ................ ....................................... 327 LITERATURE CITED ....................................................... 327

Interaction of penicillin with the bacterial cell: penicillin-binding proteins and penicillin-sensitive enzymes.

Demonstration of molecular interactions between the murein polymerase PBP1B, the lytic transglycosylase MltA, and the scaffolding protein MipA of Escherichia coli.

Lars Burman

Papers

FL-1060: a new penicillin with a unique mode of action.