Outer Membrane Proteins as Potential Anti‐infective Drug Targets in Mannheimia haemolytica

Abstract

Mannheimia haemolytica is considered to be the most important bacterial pathogen associated with BRD (bovine respiratory disease) and is responsible for substantial economic losses to the livestock industries. Antibiotics play a primary role in the treatment and control of pneumonic pasteurellosis and BRD; they are used both therapeutically and metaphylactically. The antibiotics ceftiofur, enrofloxacin, danofloxacin, tulathromycin, tilmicosin, florfenicol, chlortetracycline, and oxytetracycline are commonly used in the treatment and control of pneumonic pasteurellosis and BRD. However, the emergence and spread of antibiotic resistance in M. haemolytica and other BRD pathogens is becoming an increasing problem. A further worrying trend in the development of antibiotic resistance in M. haemolytica is the transfer of multiple resistance determinants by integrative conjugative elements (ICEs). Therefore, there is an urgent need to design and develop new antibacterial agents against this economically important pathogen. The identification of new antibiotics is likely to involve a combination of cell- and target-based approaches. Novel drug targets do not need to be part of central metabolic processes and could include virulence genes. It will be important that the development of new antibiotics should also involve appropriate in vivo screening because in vivo growth has a profound effect on gene transcription and will affect the expression of potential drug targets. The outer membrane of Gram-negative bacteria contains in excess of 100 proteins with a wide range of functions ranging from outer membrane biogenesis and integrity to drug efflux, iron transport, and adherence; the outer membrane is at the interface between the bacterium and host, and many of these proteins play key roles in host–pathogen interactions. Therefore, many of these proteins represent potential drug targets that could be the focus for future research aimed at the design and development of new drugs to combat M. haemolytica and the other pathogens responsible for BRD.